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359 publications mentioning hsa-mir-141 (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-141. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 485
Other miRNAs from this paper: mmu-mir-141, mmu-mir-150, hsa-mir-150, hsa-mir-196b, mmu-mir-196b
Western blot analysis showed that upregulating miR-141-3p reduced the expression of mesenchymal marker vimentin and fibronectin, and enhanced the expression of epithelial marker E-cadherin in PCa cells; conversely, silencing miR-141-3p increased vimentin and fibronectin expression, and decreased E-cadherin expression (Fig. 3c). [score:12]
Real-time PCR analysis showed that upregulating miR-141-3p inhibited the expression levels of multiple NF-κB signaling downstream metastasis-related target genes, including Vimentin, SNAIL2, MMP13 TWIST1 and IL11 in PCa cells. [score:10]
The effects of miR-141-3p on NF-kB activity and Vimentin, SNAI2 and TWIST1 expression are TRAF targeting dependent in PCa cells (A) Upregulating TRAF5, TRAF6 or both partially rescued the NF-kB activity repressed by miR-141-3p-overexpression in PCa cells. [score:10]
The relative expressions of miR-141-3p and these proteins were used to perform the correlation analysis Through analyzing the miRNA sequencing dataset of PCa from The Cancer Genome Atlas (TCGA), we found that miR-141-3p expression was downregulated in bone metastatic PCa tissues compared with that in non-bone metastatic PCa tissues (Fig.   1a), and the percentage of low expression of miR-141-3p was higher in bone metastatic PCa tissues than that in non-bone metastatic PCa tissues (Fig. 1b). [score:9]
Our results further demonstrate that ectopic expression of miR-141-3p suppresses activity of NF-κB signaling via targeting TRAF5 and TRAF6, which further inhibits invasion, migration and bone metastasis in PCa. [score:9]
Our results further show that miR-141-3p inhibits the activation of NF-κB signaling via directly targeting tumor necrosis factor receptor -associated factor 5(TRAF5) and 6 (TRAF6), which further suppresses invasion, migration and bone metastasis of PCa cells. [score:8]
Furthermore, upregulating TRAF5, TRAF6 or both partially rescued the NF-κB activity, and Vimentin, SNAI2 and TWIST1 expression repressed by miR-141-3p-overexpression in PCa cells (Additional file  8: Figure S4A-D). [score:8]
We further overexpressed and downregulated miR-141-3p via transient transfection in VCaP and C4-2B cells that express moderate level of miR-141-3p (Fig. 3b). [score:8]
Our results further indicate that miR-141-3p inhibits NF-κB signaling in PCa cells via directly targeting TRAF5 and TRAF6, which further suppresses bone metastasis of PCa. [score:8]
In summary, our results demonstrate that downexpression of miR-141-3p promotes the development of bone metastasis in PCa via upregulating TRAF5 and TRAF6, resulting in the sustained activity of NF-κB signaling. [score:7]
Importantly, miR-141-3p expression levels has been reported to be downexpressed in bone metastatic PCa cells PC-3 [29], suggesting that low expression of miR-141-3p plays an important role in the bone metastasis of PCa. [score:7]
Through analyzing the miRNA sequencing dataset of PCa from The Cancer Genome Atlas (TCGA), we found that miR-141-3p expression was downregulated in bone metastatic PCa tissues compared with that in non-bone metastatic PCa tissues (Fig.   1a), and the percentage of low expression of miR-141-3p was higher in bone metastatic PCa tissues than that in non-bone metastatic PCa tissues (Fig. 1b). [score:7]
As shown in Fig. 4d-f, upregulating miR-141-3p inhibited the invasion and migration abilities of PCa cells. [score:6]
e Upregulating miR-141-3p converted a stick-like or long spindleshaped mesenchymal profile to a cobblestone-like or a short spindle-shaped epithelial morphology in VCaP and C4-2B cells treated with TGF-β (5 ng/ml for 72 h) GSEA analysis further revealed that downexpression of miR-141-3p positively correlated with metastatic propensity (Fig.   4a-c). [score:6]
RT-PCR and western blotting analysis revealed that upregulating miR-141-3p reduced, while silencing miR-141-3p increased the expression levels of TRAF5 and TRAF6, but not of TRAF1 in PCa cells (Fig. 5b and Additional file  7: Figure S3A-C). [score:6]
Upregulating miR-141-3p inhibits bone metastasis of PC-3 cells in vivo. [score:6]
Fig. 3Upregulation of miR-141-3p inhibits EMT in PCa cells. [score:6]
In turn, downexpression of miR-141-3p constitutively activated NF-κB signaling through upregulating TRAF5 and TRAF6 in PCa cells. [score:6]
Fig. 2Upregulation of miR-141-3p inhibits bone metastasis of PC-3 cells in vivo. [score:6]
In this study, our results found that miR-141-3p directly suppressed the expression of TRAF5 and TRAF6, which further constrained the NF-kB signaling activity. [score:6]
Collectively, these finding demonstrate that upregulating miR-141-3p inhibits the bone metastasis of PCa in vivo. [score:6]
Furthermore, upregulating miR-141-3p suppresses the EMT, invasion and migration of PCa cells in vitro. [score:6]
Importantly, upregulating miR-141-3p significantly inhibits bone metastasis of PC-3 cells in vivo. [score:6]
Consistently, miR-141-3p expression was differentially downexpressed in PCa cells compared with normal prostate epithelial cells RWPE-1, except for lymph node metastatic cell line LNCaP, and the lowest expression level of miR-141-3p was observed in bone metastatic PCa cell lines PC-3 (Fig. 1e). [score:6]
To further investigate the clinical significance of miR-141-3p -induced TRAF5 and TRAF6 downregulation and the subsequent activation of NF-κB signaling in PCa tissues, miR-141-3p expression and the protein expression levels of TRAF5, TRAF6 and nuclear p65 were examined. [score:6]
We further examined the expression levels of miR-141-3p in our PCa tissues and found that the miR-141-3p expression level in bone metastatic PCa tissues was dramatically decreased compared with that in non-bone metastatic PCa tissues (Fig. 1c), and the percentage of low expression of miR-141-3p was higher in bone metastatic PCa tissues than that in non-bone metastatic PCa tissues (Fig. 1d). [score:6]
The analysis of clinical correlation shows that miR-141-3p inversely correlates with TRAF5 and TRAF6 expression, as well as with NF-κB signaling activity and downstream target genes of NF-κB signaling in human PCa tissues. [score:5]
Thus, these results reveal that miR-141-3p inhibits NF-κB signaling pathway via targeting TRAF5 and TRAF6 in PCa cells. [score:5]
NF-κB activation is essential for the pro-metastasis role of miR-141-3p downexpression in PCa cells (A) NF-κB signaling inhibitors LY2409881 (10 μM) and JSH-23 (10 μM) attenuated the stimulatory effect of silencing miR-141-3p on NF-κB transcriptional activity in the indicated cells respectively. [score:5]
a- c GSEA revealed that low expression of miR-141-3p expression significantly correlated with metastatic propensity. [score:5]
Our results further revealed that miR-141-3p repressed the activity of NF-κB signaling via targeting TRAF5 and TRAF6, which further inhibited the EMT, invasion, migration and bone metastasis of PCa cells in vitro and in vivo. [score:5]
As shown in Fig.   6a and b, miR-141-3p overexpression inhibited, while silencing miR-141-3p increased NF-κB -dependent luciferase activity in PCa cells. [score:5]
Therefore, our results indicate that miR-141-3p inactivates NF-kB signaling via targeting TRAF5 and TRAF6, which further inhibits bone metastasis of PCa. [score:5]
Importantly, inhibition of NF-κB signaling activity by specific inhibitors of NF-κB signaling LY2409881 and JSH-23attenuated the stimulatory effects of silencing miR-141-3p on invasion and migration of PCa cells. [score:5]
Here, we reported that miR-141-3p expression was reduced in bone metastatic PCa tissues, and low expression of miR-141-3p correlated with PSA levels, Gleason grade and bone metastasis status in PCa patients. [score:5]
Therefore, our results indicate miR-141-3p plays a tumor suppressive role in bone metastasis of PCa via inhibiting NF-κB signaling. [score:5]
Importantly, a study by Liu and colleagues has demonstrated that bone metastatic PCa cells PC-3 expressed little endogenous miR-141-3p [29], suggesting that low expression of miR-141-3p may play an important role in the bone metastasis of PCa. [score:5]
The median of miR-141-3p expression in PCa tissues was used to stratify high and low expression of miR-141-3p. [score:5]
Abundant studies have shown that miR-141-3p was downexpressed in multiple human cancers, including hepatocellular carcinoma, prostate cancer, breast cancer, renal cell carcinoma, pancreatic cancer and gastric cancer and that low expression of miR-141-3p promoted cancer cell invasion and metastasis via varying mechanisms [29, 30, 43– 46]. [score:5]
Pearson analysis revealed that miR-141-3p expression inversely correlated with TRAF5, TRAF6 and nuclear p65 expression (Fig. 7b-d). [score:5]
Moreover, inhibition of NF-κB signaling by LY2409881 and JSH-23 abrogated the stimulatory effects of miR-141-3p downexpression on migration and invasion abilities in PCa cells (Additional file 9: Figure S5B and C). [score:5]
miR-141-3p expression levels were normalized to that miR-141-3p expression of sample one. [score:5]
The relative expressions of miR-141-3p and these proteins were used to perform the correlation analysis The primary results of the current study provide novel visions into the critical role of miR-141-3p in the repressive activation of NF-κB signaling, which further inhibits bone metastasis of PCa. [score:5]
a Gene set enrichment analysis (GSEA) revealed that low expression of miR-141-3p expression significantly and positively correlated with the EMT signatures. [score:5]
Ectopic expression of miR-141-3p inhibits EMT in PCa cells. [score:5]
a Predictive target genes of miR-141-3p from TargetScan, miRanda and miRDB. [score:5]
Fig. 4Upregulation of miR-141-3p represses invasion and migration abilities of PCa cells in vitro. [score:4]
Therefore, our results demonstrate that miR-141-3p directly targets TRAF5 and TRAF6 in PCa cells. [score:4]
d Upregulating miR-141-3p converted a stick-like or long spindleshaped mesenchymal profile to a cobblestone-like or a short spindle-shaped epithelial morphology in PC-3 cells. [score:4]
However, recent literatures reported that miR-141-3p was upregulated in nasopharyngeal carcinoma and acted as an oncogenic miRNA [47, 48]. [score:4]
Furthermore, upregulating miR-141-3p represses, while silencing miR-141-3p enhances EMT, invasion and migration of PCa cells in vitro. [score:4]
miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been wi dely reported to be involved in the progression and metastasis of several human cancer types. [score:4]
H&E staining of the bone tumor sections revealed that upregulating miR-141-3p reduced the tumor burden in bone (Fig. 2c). [score:4]
Furthermore, upregulating miR-141-3p reversed the scattered spindle-shaped morphology induced by TGF-β in VCaP and C4-2B cells (Fig. 3e). [score:4]
Importantly, upregulating miR-141-3p dramatically reduces bone metastasis of PC-3 cells in vivo. [score:4]
In this study, our results revealed that TRAF5 and TRAF6 were direct targets of miR-141-3p in PCa cells. [score:4]
Upregulating miR-141-3p represses migration and invasion abilities in PCa cells. [score:4]
miR-141-3p is downregulated in bone-metastatic PCa tissues. [score:4]
d The sum of bone metastasis scores for each mouse in tumor-bearing mice inoculated with vector (n = 11) or miR-141-3p -overexpressing (n = 12) cells. [score:3]
b Percentages and number of samples showed high or low miR-141-3p expression in bone metastatic and non-bone metastatic PCa tissues in PCa dataset from TCGA. [score:3]
c Predicted miR-141-3p targeting sequence and mutant sequences in 3’UTR s of TRAF5 and TRAF6. [score:3]
Real-time PCR analysis of miR-141-3p expression in VCaP and C4-2B cells treated with TGF-β (5 ng/ml for 48 h). [score:3]
In this study, we report that miR-141-3p is downregulated in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. [score:3]
Moreover, luciferase assay revealed that upregulating miR-141-3p repressed, while silencing miR-141-3p elevated the reporter activity driven by the 3’UTRs of TRAF5 and TRAF6, but not by the mutant 3’UTR of TRAF5 and TRAF6 within the miR-141-3p–binding seed regions in PCa cells (Fig. 5c-f). [score:3]
miR-141-3p expression was not affect by TGF-β treatment (Additional file  6: Figure S2). [score:3]
The luciferase-labeled vector or miR-141-3p -overexpressing PC-3 cells were inoculated respectively into the left cardiac ventricle of male nude mice to monitor the progression of bone metastasis by bioluminescence imaging (BLI). [score:3]
b- d Correlation between miR-141-3p levels and TRAF5, TRAF6 and nuclear p65 expression in PCa and bone tissues. [score:3]
The clinical negative correlation of miR-141-3p expression with TRAF5, TRAF6 and NF-κB signaling activity is demonstrated in PCa tissues. [score:3]
Low expression of miR-141-3p was positively associated with serum PSA level, Gleason grade and distant bone metastasis status in PCa patients. [score:3]
miR-141-3p suppresses NF-kB activity in PCa cells. [score:3]
Taken together, these findings clarify a novel mechanism responsible for constitutive activation of NF-κB signaling in bone metastasis of PCa, determining that miR-141-3p play a tumor-suppressive role in bone metastasis of PCa. [score:3]
Furthermore, low expression of miR-141-3p has been reported to be closely associated with metastatic phenotype of cancers [49, 50]. [score:3]
Moreover, cellular fractionation and western blotting analysis revealed that overexpression of miR-141-3p decreased, while silencing miR-141-3p promoted nuclear accumulation of NF-κB/p65 (Fig. 6c and d). [score:3]
of PCa tissue samples demonstrated that low expression of miR-141-3p positively correlated with serum PSA levels, Gleason grade and bone metastasis status in PCa patients (Additional file 3: Table S3 and Additional file  4: Table S4). [score:3]
Conversely, silencing miR-141-3p enhanced expression levels of these genes in PCa cells (Fig. 6e-g). [score:3]
d Upreulating miR-141-3p suppressed invasion and migration abilities in PC-3 cells. [score:3]
Clinical correlation of miR-141-3p with its targets was examined in clinical PCa tissues. [score:3]
miR-141-3p expression was examined in 89 non-bone metastatic and 52 bone metastatic PCa tissues by real-time PCR. [score:3]
NF-κB activation is essential for the pro-metastasis role of miR-141-3p downexpression in PCa cells. [score:3]
These results indicate that miR-141-3p inhibits EMT in PCa cells. [score:3]
These results indicate that miR-141-3p inhibits invasion and migration abilities in PCa cells. [score:3]
These results suggest that low expression of miR-141-3p strongly correlates with the bone metastasis of PCa. [score:3]
d- f of cells transfected with pmirGLO-3’UTR reporter of TRAF5 and TRAF6 in the miR-141-3p overexpressing and silencing PCa cells. [score:3]
a Representative BLIs signal of bone metastasis of a mouse from the vector or miR-141-3p -overexpressing groups of mice at 12 mins and 8 week respectively. [score:3]
Low expression of miR-141-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. [score:3]
a Analysis of miR-141-3p expression with TRAF5, TRAF6 and nuclear p65 in 4 non-bone metastatic PCa tissues (T1–4) and 4 bone metastatic PCa tissues (T5–8). [score:3]
d Percentages and number of samples showed high or low miR-141-3p expression in bone metastatic and non-bone metastatic PCa tissues in our PCa tissues. [score:3]
miR-141-3p targets TRAF5 and TRAF5. [score:3]
e Real-time PCR analysis of miR-141-3p expression levels in normal prostate epithelial cell (RWPE-1), primary PCa cell 22RV1, bone metastatic PCa cell lines (PC-3, C4-2B and VCaP) and brain metastatic cell line DU145 and lymph node metastatic cell line LNCaP. [score:3]
c Real-time PCR analysis of miR-141-3p expression in 89 non-bone metastatic and 52 bone metastatic PCa samples. [score:3]
e Quantification of the BLI signaling in the vector and miR-141-3p -overexpressing groups at 6, 7 and 8 weeks respectively. [score:3]
In this study, our results revealed that miR-141-3p expression was reduced in human bone metastatic PCa tissues and cells. [score:3]
Taken together, expression level of miR-141-3p negatively correlates with TRAF5, TRAF6 and NF-κB activation in clinical PCa tissues. [score:3]
Clinical relevance of miR-141-3p with the expression of downstream genes of NF-κB signaling in PCa tissues. [score:3]
a miR-141-3p expression levels was decreased in bone metastatic PCa tissues (PCa/BM) compared with that in non-bone metastatic PCa tissues (PCa/nBM) as assessed by analyzing the TCGA PCa miRNA sequencing dataset (PCa/nBM, n = 11; PCa/BM, n = 9). [score:2]
As shown in Fig.   2a and b, the miR-141-3p -overexpressing PC-3 cells presented lower bone metastasis ability compared with the control group by X-ray and BLI. [score:2]
Bioinformatics analysis, Western blot, luciferase reporter and assays were performed to explore and examine the relationship between miR-141-3p and its potential targets. [score:2]
Thus, in-depth of understanding the specific role of miR-141-3p in the pathogenesis of PCa bone metastasis will facilitate the development of novel therapeutic methods for the treatment of PCa bone metastasis. [score:2]
As one of the originally discovered miRNAs, dysregulation of miR141-3p is implicated in the progression and metastasis of various cancers [29, 30]. [score:2]
Moreover, cells with miR-141-3p overexpression exhibited fewer bone metastatic sites and smaller osteolytic area of metastatic tumors, as well as longer survival and bone metastasis-free survival compared to the control group (Fig. 2d-g). [score:2]
As shown in Fig.   7a, miR-141-3p expression in bone metastatic PCa tissues (T5–8) was reduced compared with that in non-bone metastatic PCa tissues (T1–4) (Fig. 7a). [score:2]
The effect of miR-141-3p on the morphology of PCa cells was investigated and the result showed that upregulating miR-141-3p converted the stick-like or long spindle shaped mesenchymal phenotype to an evident short spindle-shaped or cobblestone-like epithelial profile in PC-3 cells (Fig. 3d). [score:2]
Real-time PCR analysis of miR-141-3p expression in PC-3 cells transduced with pre-miR-141 compared to controls. [score:2]
Anti-miR-141-3p, small interfering RNA (siRNA) for the TRAF5 and TRAF6 knockdown and corresponding control siRNAs were synthesized and purified by RiboBio. [score:2]
miR-141-3p expression is reduced in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. [score:2]
b Real-time PCR analysis of miR-141-3p expression inVCaP and C4-2B cells transduced with miR-141-3p or transfected with anti-miR-141-3p compared to controls. [score:2]
Fig. 7Clinical relevance of miR-141-3p with TRAF5, TRAF6 and NF-kB signaling activity in human PCa and bone tissues. [score:1]
Clinical correlation of miR-141-3p with TRAF5, TRAF6 and NF-κB activation in human PCa tissues. [score:1]
However, the clinical significance and biological roles of miR-141-3p in the bone metastasis of PCa remain unclear. [score:1]
Conversely, silencing miR-141-3p enhanced the invasion and migration abilities of PCa cells. [score:1]
The human miR-141-3p gene was PCR-amplified from genomic DNA and cloned into a pMSCV-puro retroviral vector (Clontech, Japan). [score:1]
The chi-square test was used to analyze the relationship between miR-141-3p expression and clinicopathological characteristics. [score:1]
However, the clinical significance and biological roles of miR-141-3p in bone metastasis of PCa are still unclear. [score:1]
miR-141-3p EMT Bone metastasis NF-κB signaling and prostate cancer Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in men [1]. [score:1]
Conversely, silencing miR-141-3p yields an opposite effect. [score:1]
miR-141-3p expression inversely correlates with the clinicopathological characteristics and bone metastasis status in PCa patients. [score:1]
However, the clinical significance and biological roles of miR-141-3p in bone metastasis of PCa remain largely unknown. [score:1]
Our findings unravel a novel mechanism underlying the bone metastasis of PCa, suggesting that miR-141-3p mimics might represent a potential therapeutic avenue for the treatment of PCa bone metastasis. [score:1]
Consistently, miR-141-3p levels in PCa tissues were negatively associated with mRNA levels of the NF-κB signaling downstream genes MMP13, TWIST1 and IL11 (Additional file  10: Figure S6A-C). [score:1]
Collectively, our findings indicate that miR-141-3p plays an important role in the bone metastasis of PCa. [score:1]
These results indicate that NF-κB signaling activation is essential for the pro-metastasis role of miR-141-3p silencing in PCa cells. [score:1]
Importantly, individual silencing of TRAF5 and TRAF6 abrogated the stimulatory effects of silencing miR-141-3p on invasion and migration abilities in PCa cells (Additional file 7: Figure S3D and E). [score:1]
As shown in Additional file  9: Figure S5A, the stimulatory effects of miR-141-3p silencing on NF-κB activity were attenuated by LY2409881 and JSH-23 in PCa cells. [score:1]
These studies indicate that the pro- and anti-cancer roles of miR-141-3p are tumor-type dependent. [score:1]
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[+] score: 414
The correlation of low miR-141 expression with high HOTAIR expression in human glioma patients is consistent with our finding that overexpression of miR-141 can downregulate HOTAIR in glioma cells (Figure 3G). [score:10]
HOTAIR mRNA expression was markedly decreased by transfection of miR-141 mimic, and was upregulated by transfecting miR-141 inhibitor in U87 and U251 glioma cells (Figure 3D). [score:8]
Here, we presented strong evidence that miR-141 could inhibit the expression of HOTAIR by combining directly to the 3′UTR of HOTAIR in glioma cells, and an inverse correlation between miR-141 and HOTAIR expression in glioma tissues. [score:8]
The MSP result showed that compared with normal brain tissues, the promoter CpG islands of miR-141 were hypermethylated in low grade and high glioma specimens which miR-141 expression was downregulated, strongly suggesting an essential role of promoter methylation in miR-141 down-regulation (Figure 8B). [score:8]
Taken together, our results revealed that miR-141 was abnormally down-regulated in glioma and its expression level negatively correlated with disease severity. [score:8]
To further validate this finding, we treated the cells with DNA methyltransferase inhibitor 5-AzadC for 48 h. Compared with the controls, the expression of miR-141 was significantly upregulated, and the demethylation of miR-141 in U251 and U87 glioma cells with 5-AzadC treatment (Figure 8C–8D). [score:7]
Co-transfection of miR-141 inhibitor and si-SKA2 showed that miR-141 inhibitor increased cell proliferation suppressed by si-SKA2 (Figure 6A–6B). [score:7]
The positive correlation between SKA2 and HOTAIR expression and the relevance to miR-141 expression levels supports our hypothesis that ceRNA can sequester miRNAs, thereby protecting their target mRNAs from repression. [score:7]
Both overexpression of miR-141 and knockdown of HOTAIR inhibit xenograft tumor growth in vivo. [score:6]
In an approach using a combination of in silico miRNA target prediction and target confirmation by 3′UTR luciferase assays, qRT-PCR and western blotting, we identified SKA2 as a novel target of miR-141 in human glioma cells. [score:6]
Overexpression of miR-141 significantly inhibited the invasion of cells, whereas the knockdown of miR-141 enhanced cells invasion (Figure 2D). [score:6]
In this study, we provide evidence for the role of miR-141 as one of the tumor-suppressive miRNAs that is frequently downregulated in glioma samples and cell lines, through methylation of its promoter. [score:6]
Both overexpression of miR-141 and knockdown of HOTAIR inhibit xenograft tumor growth in vivoTo test the function of miR-141 in vivo, we established a xenograft tumor mo del in nude mice with LV-miR-141 and sh-HOTAIR infected U87 glioma cells. [score:6]
In addition, the invasion was promoted in miR-141 inhibitor treated glioma cells, while SKA2 knockdown reversed the invasion mediated by miR-141 inhibitor (Figure 6D). [score:6]
In the present study, we demonstrated that miR-141 expression was significantly downregulated in gliomas tissues and correlated with pathological grade of gliomas. [score:6]
To determine whether DNMT1 is involved in the methylation of miR-141 in glioma cells, the expression of DNMT1 gene was inhibited by DNMT1 RNAi (Figure 8E–8F). [score:5]
Here, we demonstrated that miR-141 significantly suppressed glioma cell proliferation, migration and invasion, whereas inhibition of miR-141 exerted the opposite effect. [score:5]
A total of 56 glioma tissues were analyzed for the expression levels of HOTAIR mRNAs and for miR-141 expression by qRT-PCR. [score:5]
Hence, the downregulation of HOTAIR by miR-141 was directly dependent on the recognition site in the HOTAIR 3′UTR in glioma cells. [score:5]
These observations imply that miR-141 may be a tumor suppressor miRNA and therapeutic target in gliomas. [score:5]
The expression of HOTAIR mRNA was observed after transfection with miR-141 mimic or miR-141 inhibitor. [score:5]
MiR-141–mediated regulation of HOTAIR expression in U87 and U251 glioma cells was further verified by HOTAIR mRNA expression analysis using qRT-PCR. [score:5]
We further demonstrated that miR-141 inhibited the proliferation, migration and invasion by targeting the 3′-UTR of SKA2 in human glioma cells. [score:5]
On the basis of miRNA target prediction databases such as TargetScan, miR-141 has the predicted seed matches in the 3′UTR of SKA2 (Figure 5A). [score:5]
In vivo experiments also confirmed that miR-141 inhibited xenograft tumor growth by targeting SKA2. [score:5]
As shown in Figure 1A, the levels of miR-141 expression in glioma tissues (n = 56) were significantly down-regulated compared with normal brain tissues (n = 11). [score:5]
In conclusion, our findings from the present study strongly suggest the involvement of HOTAIR in abnormal expression of miR-141 mediated by epigenetic modification targeted SKA2 in glioma (Figure 10). [score:5]
SKA2 is a direct target miR-141. [score:4]
To verify that SKA2 is a direct target of miR-141 in U87 and U251 cells, the 3′UTR of SKA2 with wild type or mutant seed sequence recognizing sites was cloned to a dual-luciferase reporter. [score:4]
The down-regulation of miR-141 due to the hypermethylation of its promoter region in glioma. [score:4]
HOTAIR regulate miR-141 target, SKA2. [score:4]
Recently, epigenetic modification of miR-141 has been detected in breast cancer cell, correlating with their downregulation [13]. [score:4]
We investigated whether the downregulation of miR-141 expression in glioma was caused by an epigenetic mechanism. [score:4]
It is worth mentioning that HOTAIR may act as endogenous sponge RNA and sequester a handful of miRNAs, while miR-141 is also able to regulate multiple targets. [score:4]
These results may imply that the tumor-suppressive function of miR-141 is partly through negative regulation of HOTAIR in glioma. [score:4]
For example, miR-141 has been found to be up-regulated in ovarian cancer and colon cancer, and acts as an oncogene [24, 25]. [score:4]
miR-141 is downregulated in glioma samples and glioma cells. [score:4]
Data from the MTT assay showed that miR-141 inhibitor promoted and si-SKA2 suppressed glioma cell proliferation. [score:4]
While the other studies show that miR-141 is downregulated in pancreatic cancer, renal cell carcinoma and gastric cancer [26– 28]. [score:4]
To examine if HOTAIR is involved in regulation of miR-141 target genes, the SKA2 3′UTR construct was subsequently transfected together with HOTAIR and miR-141 mimic in U87 and U251 glioma cells. [score:4]
MTT assay showed that miR-141 mimic significantly inhibited cells proliferation both in U251 and U87 cells, whereas miR-141 inhibitor promotes cell growth in both cell lines (Figure 2A–2B). [score:4]
These findings suggest that the downregulation of miR-141 may be due to the hypermethylation of miR-141 promoter. [score:4]
HOTAIR regulates the miR-141 target, SKA2. [score:4]
Consistent with HOTAIR sequestration of miR-141, showed that HOTAIR actually regulated SKA2 protein expression both in vitro and in vivo. [score:4]
Together, these results suggest that HOTAIR may act as a competing endogenous RNA (ceRNA) for the target SKA2 through binding miR-141, thereby regulating the derepression of SKA2. [score:4]
As illustrated in Figure 7G–7H, DNMT1 knockdown with RNAi in U251 and U87 glioma cells ameliorated miR-141 methylation, and restored miR-141 mRNA expression. [score:4]
The present work provides specific epigenetic regulatory network between methylation, miRNA, and lncRNA, suggesting a novel strategy for the prevention and treatment of gliomas based on targeting miR-141 and its downstream HOTAIR. [score:4]
In accordance with the fact that HOTAIR promotes malignancy, whereas miR-141 suppresses malignancy in a variety of tumors [33, 34]. [score:3]
SKA2 is downstream target of miR-141. [score:3]
To determine the levels of miR-141 in glioma samples and cell lines, total RNAs were extracted from glioma tissues at grades I, II, III, and IV, normal brain tissue samples and glioma cell lines, and the expression levels of miR-141 were analyzed using qRT-PCR. [score:3]
Figure 4(A) HOTAIR restores clone formation which is suppressed by miR-141 mimic in U87 and U251 glioma cells. [score:3]
To explore whether there is any association between the loss of miR-141 and the pathogenesis of glioma, we detected the expression of miR-141 in glioma tumor samples with different histopathologic grades and found a significant decrease in low grade glioma samples, whereas a much stronger decrease was observed in high grade glioma samples, suggesting that miR-141 may be involved in pathogenesis of glioma (Figure 1B). [score:3]
The relationship between the expression of HOTAIR, SKA2 and miR-141 in tissues was analyzed with Pearson's correlation. [score:3]
Effect of DNA methylation on miR-141 expression. [score:3]
HOTAIR expression is inversely correlated with miR-141 in human glioma tissues. [score:3]
By using similar strategies as described in previous study [23], HOTAIR was predicted as one of the targets of miR-141 (Figure 3A). [score:3]
To validate whether HOTAIR is target of miR-141 in U87 and U251 glioma cells, we constructed luciferase reporter plasmid containing 3′UTR for HOTAIR. [score:3]
Interestingly, HOTAIR may act as a ‘sponge’ of miR-141, thereby modulating expression of SKA2 in glioma. [score:3]
Similarly, the inhibition of glioma cells invasion mediated miR-141 mimic was in part rescued HOTAIR (Figure 4C). [score:3]
Because miR-141 could repress the expression of HOTAIR, we investigated whether an inverse relationship existed between miR-141 expression and levels of HOTAIR. [score:3]
Figure 5(A) Predicted binding of miR-141 to the 3′UTR of human SKA2 by TargetScan. [score:3]
As shown in Figure 3B–3C, ectopic expression of miR-141 markedly decreased the reporter luciferase activities. [score:3]
MiR-141 as a candidate tumor suppressor miRNA related to the pathogenesis and progression of human gliomas. [score:3]
Furthermore, our analyses demonstrated that miR-141 inhibited the proliferation and invasiveness of glioma cells, whereas HOTAIR reversed the effects that miRNA-141 exerted. [score:3]
We further examined SKA2 mRNA and protein expression in U87 and U251 cells after transfection of miR-141 mimic. [score:3]
The loss of miR-141 expression in gliomas. [score:3]
The wound healing assay showed that miR-141 overexpression exhibited considerably slower migration and reduced cell spreading of both U87 and U251 cells, whereas miR-141 knockdown boosted cell migration in both cell lines (Figure 2C). [score:3]
Chiyomaru et al reported that HOTAIR is one of the downstream targets of miR-141 in renal carcinoma cells [23]. [score:3]
The results showed that the relative luciferase activity of the plasmid carrying SKA2 3′UTR-WT was significantly suppressed in the presence of miR-141 mimic. [score:3]
Recently, Liu et al. reported that miR-141 inhibited malignant biological phenotype of hepatocellular carcinoma cells, but in contrast to other studies that suggested miR-141 acted as an oncogene in nasopharyngeal carcinoma [29, 30]. [score:3]
Collectively, these results indicated that miR-141 strongly inhibited the proliferation and invasion of glioma cells. [score:3]
Figure 1(A) miR-141 expression in glioma and normal brain tissues by qRT-PCR. [score:3]
Therefore, these results suggest that miR-141 acts its tumor suppressor roles by SKA2 in glioma cells. [score:3]
Western blot analyses showed that SKA2 expression was decreased in the LV-miR-141 and sh-HOTAIR xenograft tumor (Figure 9E). [score:3]
Figure 7(A) The 3′UTR of SKA2 was fused to the luciferase coding region (psiCHECK-SKA2 3′UTR) and transfected in U87 and U251 glioma cells with miR-141mimic to verify SKA2 is the target of miR-141. [score:3]
miR-141 targets and negatively is correlated with HOTAIR. [score:3]
Furthermore, mutagenesis in miR-141 target sites of the HOTAIR 3′UTR linked to the luciferase reporter confirmed the site-specific effect of miR-141 (Figure 3B–3C). [score:3]
miR-141 suppresses cell proliferation, migration, and invasion in U87 and U251 glioma cells. [score:3]
We demonstrated that miR-141 mimic suppressed the clone formation of glioma cells while HOTAIR reversed the decrease in clone formation (Figure 4A). [score:3]
As shown in Figure 8A, the miR-141 was localized in the cellular nucleus and cytoplasm in low grade glioma tissues, however, high grade glioma tissues lacked miR-141 expression. [score:3]
psiCHECK-SKA2 3′UTR and miR-141 mimic constructs were co -transfected into cells with plasmids expressing HOTAIR or with a control vector to confirm the ceRNA activity of HOTAIR. [score:3]
In the present study, we demonstrated that 5-AzadC treatment induced the demethylation of miR-141, and restored miR-141 expression in glioma cells. [score:3]
These findings suggest that the loss of miR-141 expression probably attributed, at least in part, to epigenetic modification by the hypermethylation of miR-141 promoter in gliomas. [score:3]
miR-141 inhibitors group. [score:3]
It was also shown that miR-141 was down-regulated in 3 glioma cell lines, compared with 6 normal brain tissues (Figure 1C). [score:3]
We found that miR-141 mimic reduced SKA2 mRNA and protein expression (Figure 5D–5F). [score:3]
Glioma cells were transfected with miR-141 mimic, miR-141 inhibitor or si-NC. [score:3]
As shown in Figure 4B, Transwell assays analysis indicated that miR-141 mimic inhibited the migration of glioma cells while HOTAIR rescued the migration. [score:2]
miR-141's antitumor activity is in part through negative regulation of HOTAIR. [score:2]
To investigate whether HOTAIR regulated miR-141 target gene SKA2, U87 and U251 cells were transfected with HOTAIR or si-HOTAIR. [score:2]
QRT-PCR analyses showed that miR-141 was significantly increased in cells transfected with miR-141 mimic and decreased in the miR-141 inhibitor -transfected group compared with scramble (Figure 1D). [score:2]
MiR-141 inhibits glioma cells proliferation, migration and invasion. [score:2]
Figure 6(A– B) MTT assay was performed to detect the proliferation after co -transfected with miR-141 inhibitors and si- SKA2. [score:2]
To test whether miR-141 expression influences the invasive behavior of U87 and U251 glioma cells, we performed transwell assays. [score:2]
Clone formation assay demonstrated that miR-141 knockdown promoted clone formation in glioma cells, while cotransfection with si-SKA2 moderated the effect of miR-141 knockdown (Figure 6C). [score:2]
A schematic mo del of methylation of miR-141 mediated by DNMT1 regulates SKA2 by an endogenous ‘sponge’ HOTAIR in glioma. [score:2]
To investigate the miRNA-related functions of HOTAIR in glioma, we chose miR-141 as a mo del miRNA for further studies, with a particular focus on the target gene SKA2. [score:1]
To examine if the effect of miR-141 on cell proliferation and invasion is mediated by HOTAIR, we co -transfected U87 and U251 cells with HOTAIR plasmid and miR-141 mimic. [score:1]
These results suggest that HOTAIR is involved in miR-141 -mediated proliferation and invasion potential in glioma. [score:1]
H&E staining showed decreased cell density in LV-miR-141 and sh-HOTAIR xenografts (Figure 9E). [score:1]
Moreover, Epigenetic inactivation of miR-141 is a common event in glioma. [score:1]
To explore whether miR-141 exerts biological functions by SKA2, we performed a rescue experiment. [score:1]
However, the exact role of miR-141 in gliomas has not yet been elucidated. [score:1]
Nude mice were subcutaneously injected with LV-miR-141 or sh-HOTAIR transfected U87 cells. [score:1]
However, the function of miR-141 in gliomas has not yet been elucidated. [score:1]
These results suggest that miR-141 reduces the in vivo proliferation capacity of glioma cells, which is associated with HOTAIR. [score:1]
Figure 9In vivo tumor xenografts studyNude mice were subcutaneously injected with LV-miR-141 or sh-HOTAIR transfected U87 cells. [score:1]
HOTAIR may act as an endogenous ‘sponge’ by binding miR-141, thereby abolishing the miRNA -induced repression of SKA2. [score:1]
Next, we investigated whether HOTAIR mRNA expression was inversely correlated with levels of miR-141 in glioma tissues. [score:1]
MiR-141 is a member of the miR-200 family that can affect malignant phenotype of tumor cells [12]. [score:1]
The number of PCNA and Ki67 positive cells significantly reduced in the LV-miR-141 and sh-HOTAIR xenograft tumor tissues (Figure 9F). [score:1]
Here, we showed that DNMT1 was involved in epigenetic repression of miR-141 in glioma cells. [score:1]
Human glioma cells (1 × 10 [4]) grown in a 96-well plate were co -transfected with 150 ng of the corresponding psiCHECK2 plasmid, 50 nM miR-141 mimic or mimic NC, and comprising 3′UTR of SKA2, wild type or mutant HOTAIR or SKA2 fragment using Lipofectamine 2000 (Invitrogen, USA) as the transfection reagent. [score:1]
As shown in Figure 9A–9D, both LV-miR-141 and sh-HOTAIR significantly reduced xenograft tumor growth. [score:1]
MiR-141 regulates glioma cells proliferation and invasion in part by HOTAIR. [score:1]
To investigate the role of miR-141 in glioma, U251 and U87 glioma cells were transiently transfected with miR-141 mimic, miR-141 inhibitor or scramble. [score:1]
Ltd, Shanghai, China) containing miR-141 (LV-miR-141) and sh-HOTAIR were used to infect U87 glioma cells according to the manufacturer's instructions. [score:1]
Recent data have shown that miR-141 plays important roles in tumorigenesis. [score:1]
SKA2 mediated the effect of miR-141 on glioma cells. [score:1]
ISH with anti-miR-141 probe was performed to determine the localization of miR-141 in low grade glioma and high grade glioma. [score:1]
Figure 3(A) miR-141 binding sequence in HOTAIR. [score:1]
After co-transfection of miR-141 mimic or scramble with SKA2 3′UTR-Wt or SKA2 3′UTR-Mut plasmid to U87 and U251 glioma cells, luciferase activity was analyzed. [score:1]
To test the function of miR-141 in vivo, we established a xenograft tumor mo del in nude mice with LV-miR-141 and sh-HOTAIR infected U87 glioma cells. [score:1]
These results suggest that the loss of miR-141 is dependent on DNMT1 in glioma cells. [score:1]
We showed that miR-141 hypermethylation was found in high grade glioma tissues. [score:1]
MiR-141 is able to directly repress and bind to HOTAIR. [score:1]
The methylation status of the miR-141 promoter region was determined by methylation-specific PCR (MSP) using bisulfite -modified DNA. [score:1]
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We also demonstrated that overexpression of miR-141-3p in glioma cells led to the decreased expression of p21 and bax by directly targeting the 3′-UTR of p53. [score:8]
The stimulation of proliferation and inhibition of apoptosis by miR-141-3p were suppressed by p53 overexpression in the presence of TMZ. [score:7]
Previous studies observed significant upregulation or downregulation of miR-141 in various types of cancers. [score:7]
This suggests that miR-141-3p inhibits the expression of p53 at the level of translation but not transcription. [score:7]
Figure 7MiR-141-3p knockdown suppresses tumor proliferation and sensitizes TMZ resistant in vivo (A) U87 cells pre -treated with a lentivirus expressing anti-miR141-3p or anti-miR-ctrl and a lentivirus containing luciferase were implanted in the brains of nude mice. [score:6]
This differential expression implies that miR-141 activates or inhibits tumors for the initial and developmental stages of cancers [27- 29]. [score:6]
As indicated in Figure 5B-5F, 5H and 5I, the effects of miR-141-3p on cell proliferation and cell cycle distribution were inhibited by p53 overexpression. [score:5]
These results demonstrated that overexpression of p53 in GBM cells expressing high levels of miR-141-3p reverses TMZ resistance. [score:5]
To understand the mechanism of miR-141-3p activity in glioblastoma, we employed the bioinformatics analytical tool miRNAWalk 2.0 and TargetScan to identify potential target genes of miR-141-3p and found that the 3′ -UTR of p53 matched the seed sequence of miR-141-3p. [score:5]
The relative luciferase activity of Wt-p53 was significantly inhibited (40%) by miR-141-3p mimics whereas that of Mut-p53 was minimally inhibited (P<0.01; Figure 4B). [score:5]
Decreased expression of miR-141-3p significantly inhibited the growth of intracranial tumors at days 14, 21, and 28 after implantation (Figure 7A and 7D). [score:5]
The EDU -positive rate in U87 and A172 cells transfected with anti-miR-141-3p was lower than that of the control group (P<0.01, Figure 2G), indicating that the proliferation of glioma cells was suppressed by inhibition of miR-141-3p. [score:5]
We also found overexpression of miR-141-3p decreased p53 protein in U251 and Ln229 cells (Supplementary Figure 2N) which the expression of p53 protein were higher, comparing to U87 and A172 cells (Supplementary Figure 2M). [score:5]
Abnormal p53 expression effectively reduced expression of bax and p21, and rescued the increased levels of bax and p21 induced by miR-141-3p mimic in both U87 and A172 cells (Figure 5G). [score:5]
miR-141-3p promotes tumor growth and inhibits cell apoptosis and cell cycle arrest through inhibition of p53 pathways. [score:5]
Moreover, we identified p53 as a direct target for miR-141-3p, and showed that p53 was decreased in GBM with a negative correlation between miR-141-3p and p53 level. [score:4]
We also found that miR-141-3p activated proliferation, cell cycle regulation, cell apoptosis, and TMZ resistance by targeting p53 in wild-type p53 glioblastoma cells. [score:4]
p53 is a direct target of miR-141-3p in glioma cells. [score:4]
MiR-141-3p knockdown inhibits tumor growth and sensitizes cells to TMZ in vivoTo further confirm the effect of miR-141-3p on glioma growth and TMZ resistance we performed an in vivo experiment using a U87 xenograft mo del. [score:4]
This result indicated that p53 is a direct target of miR-141-3p. [score:4]
miR-141-3p directly inhibits P53 in glioma cells. [score:4]
For example, miR-141 is related to ovarian tumorigenesis via targeting of p38a and regulation of the oxidative stress response [26]. [score:4]
Although miRNA -based therapeutics are still in the initial stages of development, our findings are encouraging and suggest the potential of miR-141-3p as a diagnostic/prognostic marker and novel therapeutic target for glioma. [score:4]
Xenografted tumors were induced by U87 glioma cells co-infected with lentiviruses expressing luciferase with anti-miR-141-3p or anti-miR-ctrl, with or without treatment of the mice with TMZ (6 mice per group). [score:3]
Images show representative immunohistochemical staining for p53, Ki67 and cleaved caspase 3. (A) U87 cells pre -treated with a lentivirus expressing anti-miR141-3p or anti-miR-ctrl and a lentivirus containing luciferase were implanted in the brains of nude mice. [score:3]
Thus, we provide a thought that the combination of anti-miR-141-3p plus TMZ could be an effective therapeutic strategy for suppressing the growth of glioma. [score:3]
Moreover, for clinical human glioblastoma specimens, miR-141-3p expression levels were markedly higher in the 20 high-grade glioma tissues than in five non-cancerous brain tissues or seven low-grade glioma tissues (Figure 1B). [score:3]
Our results show that miR-141-3p acts as a tumor promoter through various mechanisms, including promotion of tumor cell growth and inhibition of cell apoptosis and induction of cell cycle arrest. [score:3]
Figure 1 (A) Expression of miR-141-3p positively correlates with the WHO grade in the CGGA Public database, non-cancerous brain and GBM specimens in the TCGA Public database. [score:3]
Knockdown of miR-141-3p in U87/TMZ-R and A172/TMZ-R cells significantly increased chemosensitivity to TMZ treatment, and cell viability was remarkably suppressed by TMZ treatment with an inverse correlation with drug concentrations compared with miR-ctrl group cells. [score:3]
For orthotopic xenograft studies, 2 × 10 [5] GBM cells stably expressing anti-miR-141-3p or anti-miR-ctrl were injected intracranially into the striatum of NOD/SCID mice using a stereotactic device (coordinates: 2 mm anterior, 2 mm lateral, 3 mm depth from the dura). [score:3]
MiR-141-3p knockdown inhibits tumor growth and sensitizes cells to TMZ in vivo. [score:3]
MiR-141-3p knockdown suppresses tumor proliferation and sensitizes TMZ resistant in vivo. [score:3]
To explore the inhibition of miR-141-3p in chemotherapy response, anti-miR-141-3p or anti-miR-ctrl was transiently transfected into U87/TMZ-resistant (TMZ-R) and A172/TMZ-R cells. [score:3]
Cell viability in the presence of TMZ (100 μM) was also assayed by CCK8 at different time points, showing that knockdown of miR-141-3p significantly inhibited cell survival of both U87/TMZ-R and A172/TMZ-R cells in the presence of TMZ (Figure 3B). [score:3]
We found that transfection of p53 was sufficient to rescue miR-141-3p–induced suppression of p53 and its downstream proteins. [score:3]
To examine the biological significance of miR-141-3p in glioma, anti-miR-141-3p or anti-miR-ctrl was transiently transfected into A172 and U87 cells that express high levels of miR-141-3p. [score:3]
Images show representative immunohistochemical staining for p53, Ki67 and cleaved caspase 3. (D) U87/TMZ-R cells stably expressing anti-miR141-3p or anti-miR-ctrl and luciferase, and treated with 100μM TMZ treatments on the days as indicated were implanted in the brains of nude mice. [score:3]
Pearson’s correlation analysis revealed that p53 levels were inversely correlated with miR-141 expression levels (Pearson’s correlation R [2]=0.506, P<0.0001). [score:3]
Figure 2 (A) Relative expressions of miR-141-3p in glioma cell lines A172, U87, U251, T98, and Ln229 and normal human astrocytes. [score:3]
Wild-type (WT) and mutated putative miR-141-3p seed-matching sites in p53 3’ untranslated regions (UTR) were amplified from human cDNA by PCR and inserted into the Sac I and Hind III restriction enzyme sites of the pmiRNA-Report vector (Genechem, Shanghai, China). [score:3]
Analysis of the Kaplan–Meier survival curve for 20 cases of clinical GBM and 64 GBM tissues from the CGGA database showed that high expression of miR-141-3p (classified as higher than the medium value) was associated with decreased survival relative to those with low miR-141-3p levels (P=0.02, Figure 1C; P=0.0207, Supplementary Figure 4A). [score:3]
We treated U87/TMZ-resistant (TMZ-R) and A172/TMZ-R cells stably expressing anti-miR-141-3p or anti-miR-ctrl with different concentrations of TMZ (Figure 3A). [score:3]
It has been demonstrated that miR-141 is involved in cancer development, progression and drug resistance regulation [24, 25]. [score:3]
Our findings suggest that miR-141-3p could be a critical therapeutic target for GBM intervention. [score:3]
So even though miR-141-3p decreased expression of p53 protein, it could not promote U251 and Ln229 cells growth significantly. [score:3]
Our findings show that miR-141-3p functions as a tumor promoter by negatively targeting p53. [score:3]
Figure 4 (A) Predicted miR-141-3p target sequence in the 3’UTR of p53 and the mutant containing altered nucleotides in the 3’UTR of p53. [score:3]
These results further indicate that p53 is a functional target for miR-141-3p in glioma cells. [score:3]
Moreover, decreased expression of miR-141-3p in tumor xenografts in nude mice slowed tumor growth and prolonged the survival of the engrafted mice. [score:3]
Figure 5 (A) Relative expression of miR-141-3p in U87 and A172 cells was analyzed by qRT-PCR after transfection. [score:3]
Figure 3 (A) Cell proliferation was detected by CCK8 assays in U87/TMZ-R and A172/TMZ-R cells stably expressing anti-miR-ctrl or anti-miR-141-3p and treated with various doses of TMZ. [score:2]
Flow cytometric analysis of apoptosis showed that knockdown of miR-141-3p promoted cell apoptosis in the presence of TMZ and resulted in a higher apoptosis rate (Figure 3G and 3H). [score:2]
Knockdown of miR-141-3p in glioblastoma cells reduced proliferation and induced cell apoptosis, cell cycle arrest, and TMZ resistance. [score:2]
also found that knockdown of miR-141-3p increased cleaved caspase 3 and decreased cyclin B1, cyclin E1 and CDK2 proteins which correlated with cell apoptosis rate and cell cycle distribution (Supplementary Figure 1A and 1B). [score:2]
qRT-PCR results showed that the relative expression level of miR-141-3p in U87/TMZ-resistant (TMZ-R) and A172/TMZ-R cells treated with anti-miR-141-3p was significantly reduced compared with cells treated with anti-miR-ctrl (P<0.01 for both cell lines; Supplementary Figure 1C). [score:2]
Inhibition of miR-141-3p had remarkable inhibitory effects on cell viability in U87 and A172 cells compared with the control group by CCK-8 assay and colony formation assay (Figure 2C-2E). [score:2]
qRT-PCR results showed that the relative expression level of miR-141-3p in U87 cells and A172 cells treated with anti-miR-141-3p was significantly reduced compared with cells treated with anti-miR-ctrl (P<0.01 for both cell lines; Figure 2B). [score:2]
also found that knockdown of miR-141-3p increased cleaved caspase 3 which correlated with cell apoptosis rate (Supplementary Figure 1D). [score:2]
Moreover, knockdown of miR-141-3p enhanced the chemosensitivity of human glioma cells to TMZ treatment and induced glioma cell apoptosis. [score:2]
Flow cytometric analysis showed that knockdown of miR-141-3p promoted cell apoptosis, increased the apoptosis rate, induced G1/S arrest, and decreased the percentage of cells in S phase (Figure 2H-2K). [score:2]
Furthermore, we showed that knockdown of miR-141-3p increased protein levels of endogenous p53 and its downstream proteins in both U87 and A172 glioma cells, but mRNA levels showed no notable change (Figure 4C and 4D). [score:2]
Figure 6 (A) Cell proliferation was detected by CCK8 assays after U87 and A172 cells were transfected with miR-ctrl or miR-141-3p with or without the p53 expression plasmid and treated with various doses of TMZ. [score:2]
MiR-141-3p expression correlates positively with malignant degrees of glioma. [score:2]
However, miR-141-3p didn’t promote glioma growth significantly in all experiments as indicated above (Supplementary Figure 2A- 2L). [score:1]
Reintroduction of p53 rescues the TMZ resistant effect of miR-141-3p. [score:1]
MiR-141 is a member of the miR-200 family, which also includes miR-200a, miR-200b, miR-200c, miR-141, and miR-429. [score:1]
Furthermore, we analyzed the correlation between p53 protein and miR-141-3p levels in all 32 tissues. [score:1]
U87 cells at a density of 10,000/well were seeded in a 24-well plate and cotransfected with wild-type (WT) or mutated (mut) reporter plasmid (100 ng), miR-141-3p mimic or miR-ctrl (50 nM) as well as internal control Renilla plasmids (100 ng). [score:1]
Hsa-miR-141-3p mimic and hsa-miR-ctrl were chemically synthesized by Ribobio (Guangzhou, China). [score:1]
U87 and A172 cells were transfected with miR-141-3p (P<0.01, Figure 5A). [score:1]
U87 and A172 cells were transfected with miR-141-3p or miR-ctrl, together with or without p53 plasmid. [score:1]
The data indicated that the expression level of miR-141-3p was significantly higher in high-grade glioma (grade III and IV) tissues compared with low-grade glioma (grades I and II) tissues from the CGGA database as well as higher in GBM compared to non-cancerous brain in the TCGA Public database (P<0.0001; Figure 1A). [score:1]
To better understand the synergistic effects of p53, U87 and A172 cells were cotransfected with miR-141-3p or miR-ctrl, together with or without p53 plasmid (Figure 4E). [score:1]
p53 reintroduction rescues the TMZ resistant effect of miR-141-3p. [score:1]
p53 reintroduction reverses the promotional effect of miR-141-3p. [score:1]
In the present study, we showed that the oncogenic miR-141-3p was increased in clinical GBM samples and correlated with WHO grade. [score:1]
In addition, the anti-miR141-3p group showed significantly longer survival (Figure 7B and 7E). [score:1]
MiR-141-3p knockdown sensitizes resistant GBM cells to TMZ. [score:1]
Interestingly, we demonstrate that miR-141-3p increases the resistance of glioma cells to TMZ treatment. [score:1]
MiR-141-3p activates glioma cell growth in vitroThe relative levels of miR-141-3p in various glioma cell lines (A172, U87, U251, T98, Ln229) and normal human astrocytes were analyzed by qRT-PCR (Figure 2A). [score:1]
In summary, the present study provides new insights into an important relationship between miR-141-3p and tumorigenesis in human glioma. [score:1]
Overall, these data indicated that miR-141-3p activates glioma cell growth and sensitizes tumors to TMZ in vivo. [score:1]
Although p53 protein was also decreased when miR-141-3p was transfected into U251 and Ln229 cells, results as indicated above were insignificant. [score:1]
We evaluated the expression level of miR-141-3p in 158 glioma tissues of different grades from the CGGA database and 255 glioma specimens of non-cancerous brain and GBM in the TCGA Public database. [score:1]
The relative levels of miR-141-3p in various glioma cell lines (A172, U87, U251, T98, Ln229) and normal human astrocytes were analyzed by qRT-PCR (Figure 2A). [score:1]
We also assessed the contribution of p53 to the TMZ resistance effect of miR-141-3p in glioma cells by co-transfection of human p53 plasmids and miR-141-3p mimics into U87 and A172 cells. [score:1]
To further confirm the effect of miR-141-3p on glioma growth and TMZ resistance we performed an in vivo experiment using a U87 xenograft mo del. [score:1]
Reintroduction of p53 could attenuate the oncogenic effect of miR-141-3p. [score:1]
Lentivirus carrying hsa-anti-miR141-3p or hsa-anti-miR -negative control (anti-miR-ctrl) was packaged in human embryonic kidney 293T cells for 48 h and harvested as instructed in the manufacturer’s manual. [score:1]
Images show representative immunohistochemical staining for p53, Ki67 and cleaved caspase 3. We evaluated the expression level of miR-141-3p in 158 glioma tissues of different grades from the CGGA database and 255 glioma specimens of non-cancerous brain and GBM in the TCGA Public database. [score:1]
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Overexpression of miR-141 inhibits EMT by directly targeting the ZEBs and enhancing E-cadherin expression (14, 23, 24). [score:10]
Chen et al (21) identified hepatoma-derived growth factor (HDGF) as a direct target of miR-141 in gastric cancer cells, and the suppressive effects of miR-141 on cancer cell migration and invasion were shown to be partially mediated by suppression of HDGF expression. [score:10]
Overexpression of miR-141 significantly reduced the mRNA and protein expression levels of ZEB2, resulting in the upregulation of E-cadherin expression. [score:10]
In renal carcinoma cell lines, overexpression of miR-141 resulted in downregulation of ZEB2 and upregulation of E-cadherin (15). [score:9]
Conversely, overexpression of miR-141 upregulated the protein expression level of E-cadherin in both cell lines (Fig. 2C). [score:8]
Furthermore, mutation of the putative miR-141 -binding sites clearly eliminated the suppression of luciferase activity caused by miR-141 overexpression (Fig. 3A, B and C). [score:6]
In addition, upregulation of miR-141 significantly inhibited gastric cancer cell proliferation (8). [score:6]
Therefore, the present study hypothesized that in gastric cancer, downregulation of miR-141 may promote EMT, cancer cell migration, and invasion by targeting the E-cadherin transcriptional repressor ZEB2. [score:6]
During EMT, the expression of the miR-200 members, including miR-141, has been shown to be significantly down-regulated (14, 23). [score:6]
These results suggest that miR-141 may suppress the metastasis of gastric cancer through its inhibitory effect on the EMT process. [score:5]
Recently, Wu et al (25) demonstrated that miR-141 functioned as a tumor suppressor via ZEB2 targeting HCC. [score:5]
As shown in Fig. 2, forced expression of miR-141 significantly reduced ZEB1/2 mRNA and protein expression levels in both HGC-27 and SGC-7901 gastric cancer cells. [score:5]
The results of the present study suggest that miR-141 may have an important role in the inhibition and migration of gastric cancer cells, by targeting ZEB2. [score:5]
miR-141 has been shown to inhibit the migration and invasion of HCC cells by targeting Tiam1 (10). [score:5]
The results suggest that the mRNA expression levels of ZEB2 may be inversely correlated with the expression levels of miR-141 in gastric tumor samples. [score:5]
In conclusion, the present study demonstrated that overexpression of miR-141 inhibited gastric cancer cell migration. [score:5]
In PC, both transmembrane 4 L six family member 1 and MAP4K4 have been reported to be directly targeted by miR-141 to regulate the invasion of PC cells (11, 20). [score:5]
The expression levels of miR-141 were upregulated by ~335 and 252 fold respectively in the HGC-27 and SGC-7901 cells transfected with miR-141 precursor, as compared with the control cells (Fig. 1A). [score:5]
The present study used HGC-27 and SGC-7901 cells as an in vitro mo del, and demonstrated that forced expression of miR-141 markedly inhibited the migration of gastric cancer cells. [score:5]
The putative miR-141 -binding sites in the ZEB2 3′-untranslated region (UTR) region were detected using Targetscan software (http://www. [score:5]
Fold change was determined as 2 [−ΔΔCt] and miR-141 expression in endoscopic samples was also normalized to U6 expression using the 2 [−ΔΔCt] method (18). [score:5]
These data suggest that miR-141 may inhibit ZEB2 protein expression through 3′-UTR at the posttranscriptional level. [score:5]
To determine whether ZEBs are a target of miR-141 in gastric cancer, alterations in ZEB1/2 expression levels were determined post-transfection with an miR-141 precursor. [score:5]
The targets by which miR-141 regulates cancer cell motility varies in different types of cancer. [score:4]
The proliferation of both cell lines was not affected by miR-141 overexpression, as determined by MTT assay (Fig. 1B) over 24 h. The in vitro migration assay (Fig. 1C and D) and wound healing assay (Fig. 1E and F) demonstrated that overexpression of miR-141 markedly inhibited the migration of HGC-27 and SGC-7901 cells. [score:4]
In our previous study, miR-141, which belongs to the miR-200 family, was shown to be downregulated in gastric cancer tissue samples and cell lines. [score:4]
Upregulation of miR-141 resulted in a significant decrease in the migration and invasiveness of HCC and PC cancer cells (10, 11, 20). [score:4]
miR-141 is a member of the miR-200 family, which has been shown to be downregulated in gastric tumor tissue. [score:4]
In CRC cells, miR-141 was shown to regulate ZEB2, and inhibit the migration and invasion of CRC cells (9). [score:4]
The results of the present study demonstrated that ZEB2 was another direct target of miR-141. [score:4]
The miR-141 target ZEB2 was negatively regulated at both the transcriptional and post-transcriptional level by miR-141. [score:4]
The expression levels of miR-141 were significantly decreased in the gastric tumor tissue samples, compared with in the non-tumor tissue samples (Fig. 4A); however, mRNA expression levels of ZEB2 were increased in the gastric cancer tissue samples (Fig. 4B). [score:4]
Therefore, the present study aimed to determine whether miR-141 targets ZEB in gastric cancer, and whether it regulates the migration of cancer cells. [score:4]
The mRNA expression levels of miR-141 and ZEB2 were detected in nine gastric tumor and non-tumor tissues by qPCR. [score:3]
Furthermore, the mRNA expression levels of ZEB2 mRNA were inversely correlated with the levels of miR-141 in gastric cancer tissue. [score:3]
miR-141 has previously been shown to function as a tumor suppressor in various cancers (9– 11, 16, 20). [score:3]
Similar findings have been obtained for colorectal cancer (CRC), as well as head and squamous cell carcinoma (9, 16), indicating that miR-141 functions as an inhibitor of cancer metastasis by decreasing the migration and invasive potential of cancer cells. [score:3]
The expression of miR-141 was detected by qPCR 24 h post-transfection. [score:3]
It has been reported that low expression of miR-141 is a significant prognostic factor for poor overall survival, both in hepatocelluar carcinoma (HCC) (10) and pancreatic cancer (PC) (20). [score:3]
Expression of ZEB2 is inversely correlated with miR-141. [score:3]
miR-141 has been shown to exclusively target ZEBs in renal, colorectal, and head and neck squamous carcinoma cells (9, 15, 16). [score:3]
Effects of miR-141 overexpression on the migration of gastric cancer cells. [score:3]
ZEB2 is a target of miR-141. [score:3]
The present study provided evidence suggesting that transfection with an miR-141 precursor suppresses the migration of gastric cancer cells. [score:3]
To further confirm whether ZEB1/2 is directly regulated by miR-141, the 3′-UTR of ZEB2 was cloned with the predicted miR-141 binding sites downstream of a luciferase reporter gene (pMIR-ZEB2), and this vector was co -transfected with the miR-141 precursor or its negative control into HGC-27 and SGC-7901 cells. [score:3]
In addition, overexpression of miR-141 significantly reduces the proliferation of gastric cancer cells (8). [score:3]
Notably, it has been demonstrated that miR-141 may inhibit cell migration and invasion in colorectal, pancreatic, and hepatocellular carcinoma (9– 11). [score:3]
It may be interesting to further explore whether miR-141 could be used as a predictive biomarker for clinical outcomes, or as a therapeutic target to prevent gastric cancer progression. [score:3]
By using a luciferase reporter assay, it was demonstrated that ZEB2 was the target of miR-141 in gastric cancer cell lines. [score:2]
In our previous study, it was demonstrated that the expression levels of miR-141 in HGC-25 and SGC-7901 gastric cancer cell lines were lower as compared to that of MGC-803 poorly-differentiated human gastric mucous adenocarcinoma and BGC-823 undifferentiated human gastric cancer cell lines. [score:2]
The mutation on the miR-141 -binding sites in human ZBE2 3′-UTR was generated by overlap PCR as described previously (17). [score:2]
The cells were transfected with miR-141 and controls as previously described. [score:1]
To determine the effects of miR-141 on cell proliferation, 5×10 [3] SGC-7901 and HGC-27 cells were transfected with either a 25 nM Pre-miR™ miR-141 precursor molecule (miR-141; Ambion Life Technologies), or a negative control #1 Pre-miR™ miRNA precursor molecule (Negative; Ambion Life Technologies), using siPORT™ Amine Transfection Agent (Ambion Life Technologies) in a 96-well plate. [score:1]
To explore the effects of miR-141 on the migration of gastric cancer cells, two human gastric mucous adenocarcinoma cell lines, HGC-27 and SGC-7901, were transfected with an miR-141 precursor or negative control precursor. [score:1]
The cells were cotrans-fected with 0.1 µg of either pMIR-ZEB2 or pMIR-REPORT, together with 20 nM miR-141 precursor molecule or 20 nM negative control #1 using siPORT amine transfection agent, according to the manufacturer's instructions. [score:1]
The SGC-7901 and HGC-27 cells (5×10 [4]) were transfected with either 25 nM miR-141 or negative control in 24-well plates for 24 h. The cells were then trypsinized and 10 [4] cells were seeded into each insert in culture medium, and the same medium was placed in the well below. [score:1]
Therefore, the present study hypothesized that miR-141 may also have a role in the migration of gastric cancer cells. [score:1]
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5
[+] score: 220
Since expression of miR-141 dramatically downregulated Keap1 (Figure 1), its effect on Nrf2 expression was then tested. [score:8]
Meanwhile, HO1 and NOQ1 expressions were also downregulated in the above miR-141 -expressing RPEs (Figure 6C and 6D). [score:8]
Two different Nrf2 shRNAs (“shNrf2-A/-B”, see Materials and Methods) with non-overlapping sequences were applied, each of them efficiently downregulated Nrf2 expression (protein and mRNA) in miR-141 -expressing RPEs (“L1/2”) (Figure 6A-6D). [score:8]
These results clearly show that forced -expression of miR-141 downregulated Keap1 in both human RPEs and RGCs. [score:6]
miR-141 expression downregulates Keap1 in human RPEs and RGCs. [score:6]
These results imply that miR-141 depletion by expressing antagomiR-141 downregulates Nrf2 and exacerbates UV damages in RPEs. [score:6]
Second, Nrf2 was stabilized in the miR-141 -expressing cells, which was evidenced by upregulation of Nrf2 protein, but not mRNA. [score:6]
First, miR-141 targeted and degradated Nrf2 inhibitor Keap1 in the above eye cells. [score:5]
Since miR-141-3p could potentially target Keap1 [14, 18, 19], we next analyzed Keap1 expression in these cells. [score:5]
In the current study, we show that microRNA-141 (“miR-141”) activates Nrf2 signaling via selectively targeting and silencing Keap1, which inhibits UV -induced oxidative stress and apoptosis in RPEs and RGCs. [score:5]
Yet, Nrf2 mRNA expression was unchanged after miR-141 expression (Figure 2B). [score:5]
miR-141 expression inhibits UV -induced ROS production in RPEs and RGCs. [score:5]
Together, miR-141 expression largely inhibits UV -induced ROS production in RPEs and RGCs. [score:5]
Intriguingly, expression of Nrf2's genes, including HO1, NQO1 and GCLC [11], were significantly increased (both protein and mRNA) following miR-141 expression in RPEs (Figure 2A and 2B). [score:5]
miRNA-141 -expressing RPEs (“L1/2”) were infected with lentiviral Nrf2 shRNA (“shNrf2-A/-B”, with non-overlapping sequence) or scramble control shRNA (“shSCR”), expression of Nrf2 mRNA (A) and (B) and listed proteins (C) and (D) were shown. [score:5]
The ROS content in miR-141 -expressing cells following was comparable to the untreated control level (Figure 4A and 4B), indicating the potent anti-oxidant activity by miR-141 expression. [score:5]
shRNA strategy was utilized to stably knockdown Nrf2 in miR-141 -expressing RPEs. [score:4]
Meanwhile, UV -induced RPE cell death (Figure 3B) and apoptosis (Figure 3C and 3D) were also largely attenuated with miR-141 expression. [score:3]
There are at least twenty-seven potential target genes of miR-141 have been characterized thus far, which were predicted by the software including PicTar, TargetScanS, and miRanda [24]. [score:3]
Collectively, miR-141 expression significantly protects RPEs and RGC from UV. [score:3]
Figure 5Expression of miRNA-141 (A) Keap1 mRNA (B) and listed proteins (B) in RPEs transfected with antagomiR-141 or non-sense control antagomiR (“antagomiR-C”) were shown. [score:3]
Importantly, activation of Nrf2 by miR-141 expression significantly ameliorated UV -induced oxidative stress and subsequent death/apoptosis of RPEs and RGCs. [score:3]
Consequently, when Nrf2 was depleted, these miR-141 -expressing RPEs became vulnerable or re-sensitive to UV (Figure 6E and 6F). [score:3]
Very similar results were also observed in RGCs, where miR-141 expression stabilized Nrf2 (Figure 2C) and promoted transcription of Nrf2's genes (two RGC lines, Figure 2C and 2D). [score:3]
RGCs or RPEs were transfected with 200 pmol of miR-141 inhibitor (“antagomiR-141”, synthesized by GenePharm, Shanghai, China) [22] or negative control antagomiR (“antagomiR-C”, GenePharm) via the Lipofectamine2000 (Invitrogen) reagents. [score:3]
Through puromycin selection, two stable ARPE-19 cell lines expressing miR-141 were established, namely “miR-141-L1” and “miR-141-L2”. [score:3]
In the current study, a miR-141 expression vector was constructed (see Materials and Methods). [score:3]
Remarkably, forced -expression of miR-141 significantly attenuated ROS production in UV -treated RPEs (Figure 4A) and RGCs (Figure 4B). [score:3]
miR-141 expression stabilizes and activates Nrf2 in human RPEs and RGCs. [score:3]
Our results showing miR-141 activates Nrf2 signaling via targeting Keap1 in RPEs and RGCs were consistent with other studies [18, 19]. [score:3]
Expression of mature hsa-miR-141-3p was examined by the same ABI Prism 7300 Fast system. [score:3]
Notably, the non-sense miRNA control (“miR-C”) had no significant effect on expression of miR-141-3p and Keap1 (Figure 1A-1D). [score:3]
miR-141 -induced cytoprotection against UV was also observed in RGCs, where miR-141 expression dramatically attenuated UV -induced viability reduction (Figure 3E) and apoptosis activation (Figure 3F). [score:3]
UV -induced a much weaker viability reduction in miR-141 -expressing RPEs (Figure 3A). [score:3]
Expression of miRNA-141 (A) Keap1 mRNA (B) and listed proteins (B) in RPEs transfected with antagomiR-141 or non-sense control antagomiR (“antagomiR-C”) were shown. [score:3]
Forced miR-141 expression. [score:3]
In this study, we showed that miR-141 expression activated Nrf2 signaling in both RPEs and RGCs. [score:3]
These results suggest that miR-141 expression induces Nrf2 stabilization and activation in RPEs and RGCs. [score:3]
RT-qPCR assay results in (Figure 5A) confirmed that antagomiR-141 transfection indeed downregulated miR-141 in the RPEs. [score:3]
miR-141 expression protects RPEs and RGCs from UV. [score:3]
miR-141 expression in these RPEs was tested. [score:3]
As demonstrated, forced -expression of miR-141 induced Nrf2 protein accumulation in RPEs (two lines, Figure 2A). [score:3]
Similarly, two stable RGC cell lines expressing miR-141 were established: miR-141-L1/L2 RGCs. [score:3]
Notably, the basal ROS content was also lower with miR-141 expression in both RPEs and RGCs (Figure 4A and 4B). [score:3]
The pre-has-miR-141 was obtained from Applied Biosystem (Shanghai, China), which was sub-cloned into pSuper-puro-GFP vector (OligoEngine, Seattle, WA) to construct miR-141 expression vector. [score:3]
These RGCs again expressed high level of miR-141 (Figure 1C), but depleted Keap1 (Figure 1D). [score:3]
Results in (Figure 1E) illustrated that miR-141-3p selectively targets the 3′ UTR of human Keap1 (Position 131-138). [score:3]
Mature has-miR-141-3p expression in the stable cells was tested by RT-qPCR assay. [score:2]
Figure 4Stable RPEs (A) and RGCs (B) expressing miR-141 (two lines, “L1/L2”) or scramble miRNA control (“miR-C”), were subjected to (30 mJ/cm [2]), cells were further cultured for 12 hours, ROS production was tested by the carboxy-H2DCFDA FACS assay, and its level was normalized to the untreated control (“Ctrl”). [score:2]
As demonstrated, Keap1 mRNA and protein expressions in miR-141-L1/L2 RPEs were sharply decreased, as compared to control parental RPEs (Figure 1B). [score:2]
shRNA -mediated knockdown of Nrf2 in these cells, on the other hand, almost abolished miR-141-cytoproteciton against UV. [score:2]
Figure 2Listed protein and mRNA expressions in stable RPEs (A) and (B) and RGCs (C) and (D) with miR-141 (two lines, “L1/L2”) or scramble miRNA control (“miR-C”) were examined by (A and C) and RT-qPCR assay (B and D), respectively. [score:2]
After 48 hours, miR-141 expression was validated by RT-qPCR assay. [score:2]
Stable RPEs (A) and RGCs (B) expressing miR-141 (two lines, “L1/L2”) or scramble miRNA control (“miR-C”), were subjected to (30 mJ/cm [2]), cells were further cultured for 12 hours, ROS production was tested by the carboxy-H2DCFDA FACS assay, and its level was normalized to the untreated control (“Ctrl”). [score:2]
Nrf2 knockdown abolishes miR-141-meidated RPE cytoprotection against UV. [score:2]
Listed protein and mRNA expressions in stable RPEs (A) and (B) and RGCs (C) and (D) with miR-141 (two lines, “L1/L2”) or scramble miRNA control (“miR-C”) were examined by (A and C) and RT-qPCR assay (B and D), respectively. [score:2]
Thus, Nrf2 stabilization and activation should be the main reason of miR-141 -induced anti-UV actions in RPEs. [score:1]
“Parental” cells) of miR-141 and Keap1 (mRNA and protein) in ARPE-19 cells (“RPEs”, same for all figures) (A) and (B) and primary human RGCs (“RGCs”, same for all figures) (C) and (D) with miR-141 (two lines, “L1/L2”) or scramble miRNA control (“miR-C”) were shown. [score:1]
MTT assay results in (Figure 3A) demonstrated that, as compared to the control cells, the two lines of RPEs with miR-141 over -expression were largely protected from UV. [score:1]
Next, antagomiR-141, an anti-sense RNA molecule complementary to miR-141 [22], was transfected to RPEs. [score:1]
The results of the current study showing that miR-141 potently activates Nrf2 signaling, which attenuates UV -induced oxidative stress and RPEs/RGCs damages. [score:1]
For example, van Jaarsveld et al., showed that miR-141 depletes Keap1 to decrease cisplatin sensitivity in ovarian cancer cells [18]. [score:1]
Above results demonstrated that miR-141 activated Nrf2 signaling in RPEs and RGCs, next we analyzed its effect on UV -induced ROS production. [score:1]
To our best knowledge, this is the first report showing potential biological functions of miR-141 in eye cells. [score:1]
We therefore conclude that miR-141 protects RPEs and RGCs from via activating Nrf2-Keap1 signaling. [score:1]
In another words, Nrf2 depletion almost abolished miR-141 -mediated cytoprotection against UV (Figure 6E and 6F). [score:1]
Remarkably, miR-141 also promoted Nrf2 nuclear translocation in RPEs (Figure 2A). [score:1]
The results above have shown that miR-141 activates Nrf2 signaling and protects cells from UV. [score:1]
Similarly, miR-141 activates Nrf2 -dependent antioxidant pathway via silencing keap1 to confer resistance to 5-FU [19]. [score:1]
The miR-141 vector was transfected to ARPE-19 cells (“RPEs”) [6, 17]. [score:1]
The miR-141 construct or the empty vector was transfected to the RPEs and RGCs through Lipofectamine 2000 reagents (Invitrogen, Shanghai, China). [score:1]
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6
[+] score: 205
Expression levels of the target genes (PTEN, ZMAT3, CCND2, CCNE2, CDK6, SIAH1) of miR-141-3p that were abundant in p53 pathway were detected, and we found that PTEN was significantly down-regulated in miR-141-3p mimics group (Fig. 5A) and up-regulated in miR-141-3p inhibitor group (Fig. 5B). [score:13]
Moreover, the miR-141-3p expression level was significantly up-regulated in the miR-141-3p mimics group and down-regulated in the miR-141-3p inhibitor group (Fig. S6D), respectively. [score:11]
In the present study, we found that (i) the expression of miR-141-3p was increased in HFD -induced obese mice liver; (ii) miR-141-3p contributed to the altered mitochondrial function, including up-regulation of ATP production, ROS production, MDA content and down-regulation of T-AOC activity, SOD activity; (iii) by silencing PTEN, ATP production was increased and oxidative stress was induced. [score:9]
To explore the effect of mitochondria-related miR-141-3p on the pro-inflammatory cytokines, we measured the expression of pro-inflammatory cytokines (IL-6 and TNF-α) in HepG2 cells, as shown in Fig. S6B, we found that the IL-6 mRNA expression level was significantly increased in the HepG2 cells transfected with miR-141-3p mimics, and reduced in the HepG2 cells transfected with miR-141-3p inhibitor, however, there was no significant difference of TNF-α mRNA expression level in the HepG2 cells. [score:7]
Taken together, exposure of the HepG2 cells to high-glucose resulted in the up-regulation of miR-141-3p expression level, suggesting that miR-141-3p was regulated by high-glucose in HepG2 cells. [score:7]
In order to test whether abnormal express of miR-141-3p will affect the mitochondrial respiratory function, we performed real-time bioenergetic kinetics, using the Seahorse extra cellular analyzer on HepG2 cells, which were transfected with miR-141-3p mimics and inhibitors. [score:5]
However, Baseler et al., found that miR-141 could decrease ATP synthase activity by inhibiting its target, solute carrier family 25 member 3 protein (Slc25a3) 19. [score:5]
Thus, in line with the two studies, our results indicated that miR-141-3p over -expression reduced PTEN expression and promoted ATP production. [score:5]
The expression level of genes (COX2, COX3) was strikingly decreased in miR-141-3p inhibitor group (Fig. 3D). [score:5]
MiR-141-3p mimics, mimics negative control, miR-141-3p inhibitor, inhibitor negative control and siRNA of PTEN oligonucleotide (Genepharm, China) were transiently transfected into HepG2 cells with the use of Lipofectamine 2000 (Invitrogen, CA, USA) according to the manufacturer’s instructions. [score:5]
The expression level of PTEN mRNA in p53 pathway was significantly decreased in the HepG2 cells transfected with miR-141-3p mimics (A) while it was significantly increased in the HepG2 cells transfected with miR-141-3p inhibitor (B) and in the HFD mice livers (C). [score:5]
To determine whether the lipid content (FFA), glucose, insulin and pro-inflammatory cytokines (interleukin 6, IL-6 and tumor necrosis factor, TNF-α) could affect miR-141-3p expression, the HepG2 cells was treated with the exogenous stimulation and miR-141-3p expression level was detected. [score:5]
In summary, present study first demonstrated that mitochondria-related miR-141-3p suppressed the expression of PTEN, resulting in HepG2 cells mitochondrial dysfunction, presumably through the elevation of ATP production, oxidative stress, and the reduction of antioxidant capacity. [score:5]
We also found that the mitochondria-related miR-141-3p might promote the pro-inflammatory cytokine (IL-6) expression, inducing the inflammatory response and contributing to the development of obesity. [score:4]
Above findings suggested that the mitochondria-related miR-141-3p might promote the pro-inflammatory cytokine (IL-6) expression, inducing the inflammatory response and contributing to the development of obesity. [score:4]
However, the possible mechanism of high-glucose in regulating miR-141-3p expression remains unknown. [score:4]
To measure the transfect efficiency of miR-141-3p mimics and inhibitors, we detected the miR-141-3p expression level in HepG2 cells before and after treatment. [score:3]
We also showed that the mitochondria-related miR-141-3p increased the expression of COX2 and COX3. [score:3]
How to cite this article: Ji, J. et al. Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD -induced obesity by inhibiting PTEN. [score:3]
To further assess the alterations of mitochondria-related miRNAs in obesity, we examined the expression levels of miR-126a-3p, miR-141-3p, miR-196a-5p, miR-210-3p, miR-378a-3p, miR-484 and miR-499a-5p in mice livers. [score:3]
As shown in Fig. S6A, after glucose stimulation in the media, the mitochondria-related miR-141-3p expression level was significantly increased. [score:3]
After transfecting miR-141-3p mimics or inhibitors, there was no significant change in the mitochondrial content (Fig. S3A, B) or the concentrations of TC (Fig. S3C, D) triglyceride (TG) (Fig. S3E, F). [score:3]
As shown in Fig. S6C, the basal expression of miR-141-3p was relatively low in the HepG2 cells. [score:3]
Recently, Roe et al., demonstrated that loss of PTEN, target of miR-141-3p, was able to increase ATP levels 21. [score:3]
The protein level of PTEN was decreased in the HepG2 cells transfected withmiR-141-3p mimics (D) while it was increased in the HepG2 cells transfected with miR-141-3p inhibitor (E). [score:3]
After transfecting miR-141-3p mimics or inhibitors, there was no significant change in the mitochondrial membrane potential (Fig. S4A-F), the cell apoptosis (Fig. S5A-F) nor the cell proliferation (Fig. S5G, H). [score:3]
The expression level of several genes (COX2, COX3, ND1) involving in OXPHOS elevated significantly in miR-141-3p mimics group (Fig. 3C). [score:3]
However, after FFA, insulin, IL-6 or TNF-α stimulation in the media, the mitochondria-related miR-141-3p expression level was higher in the treated groups, although no significant difference was detected. [score:3]
PTEN as a target of miR-141-3p. [score:3]
The oxygen consumption rates of ATP production were strikingly elevated and reduced in HepG2 cells transfected with miR-141-3p mimics and inhibitors(Fig. 3A,B), respectively. [score:3]
PTEN was the target of the mitochondria-related miR-141-3p. [score:3]
The ATP production was significantly increased in the HepG2 cells transfected with miR-141-3p mimics, while it was markedly decreased in the HepG2 cells transfected with miR-141-3p inhibitor. [score:3]
Additionally, both T-AOC and SOD activities were significantly decreased in miR-141-3p mimics group (Fig. 4E,G), while the T-AOC was partly increased and the SOD activity(Fig. 4F,H) was markedly increased in miR-141-3p inhibitor group, suggesting that miR-141-3p compromised the antioxidant defense system. [score:3]
These findings suggested that the miR-141-3p mimics and inhibitor was successfully transfected into the HepG2 cells. [score:3]
As shown in Fig. 2H, the mitochondria-related miR-141-3p expression level was significantly increased in the16-week-old HFD mice than that in the 8-week-old mice. [score:3]
In our study, miR-141-3p promoted the ATP production by targeting PTEN in HFD mice livers and hepG2 cells. [score:3]
The ROS and MDA production were found significantly increased in miR-141-3p mimics group (Fig. 4A,C), while both of them were markedly reduced in miR-141-3p inhibitor group (Fig. 4B,D). [score:3]
The ROS production (A) and MDA content (C)were both significantly increased in HepG2 cells transfected with miR-141-3p mimics and both markedly decreased in HepG2 cells transfected with miR-141-3p inhibitor (B, D). [score:3]
As shown in Fig. 2G, the expression of mitochondria-related miR-141-3p was strikingly increased and miR-196a-5p, miR-210-3p, miR-378a-3p were reduced in the HFD mice. [score:3]
Both of them were significantly decreased in HepG2 cells transfected with miR-141-3p mimics (E, G), and increased in HepG2 cells transfected with miR-141-3p inhibitor (F, H). [score:3]
The protein level of PTEN was also reduced in miR-141-3p mimics group (Fig. 5D) and increased in miR-141-3p inhibitor group (Fig. 5E), respectively. [score:3]
It demonstrated that miR-141-3p regulated PTEN by combining the 3′UTR region of PTEN mRNA. [score:2]
As the results shown (Fig. 5G), the relative luciferase activity of the HepG2 cells co -transfected with miR-141-3p mimics and pGL3-PTEN wild type was significantly inhibited when compared with the HepG2 cells co -transfected with negative control and pGL3-PTEN wild type. [score:2]
However, the role of mitochondria-related miR-141-3p in the development of obesity remains unknown. [score:2]
Then we performed dual-luciferase reporter assay to validate whether miR-141-3p regulated PTEN directly by binding to the 3′UTR region of PTEN. [score:2]
Thus, it can be hypothesized that mitochondria-related miR-141-3p might contribute to the mitochondrial dysfunction in the development of obesity. [score:2]
To further verify whether miR-141-3p affected mitochondrial function of HepG2 cells through PTEN directly, we conducted experiments with HepG2 cells transfected with PTEN siRNA. [score:2]
MiR-141-3p highly expressed in HFD mice liver. [score:2]
These findings demonstrated that miR-141-3p regulated mitochondrial activity in HepG2 cells. [score:2]
The miR-141-3p may promote mitochondrial respiratory function of HepG2 cells. [score:1]
Collectively, our study demonstrated that mitochondria-related miR-141-3p could promote OXPHOS process and increase ATP production. [score:1]
We have validated that the miR-141-3p interacted with PTEN by binding to its 3′UTR region and influenced mitochondrial function of HepG2 cells. [score:1]
With the use of this web server, we found that p53 pathway was associated with miR-141-3p. [score:1]
In conclusion, our study provided novel evidence that the miR-141-3p contributed to mitochondrial dysfunction in HFD -induced obesity. [score:1]
The sequence of 3’UTR region of PTEN predicted to interact with miR-141-3p was inserted into the XbaI site of pGL3 promoter vector (Generay, China). [score:1]
In present study, we found that mitochondria-related miR-141-3p had no impacts on mitochondrial membrane potential, cell apoptosis nor cell proliferation. [score:1]
To validate whether or not miR-141-3p regulated PTEN by binding to the 3’UTR region of PTEN mRNA, the dual-luciferase reporter assay was performed. [score:1]
Considering the most strikingly alteration of mitochondria-related miR-141-3p expression level in the mice, miR-141-3p was selected to investigate the potential mechanism involved in hepatic mitochondrial function. [score:1]
In combination with result that the higher plasma glucose level in the HFD mice, our data suggested that miR-141-3p might be involved in the obesity-related glucose intolerance. [score:1]
MiR-141-3p regulates mitochondrial function in HepG2 cells. [score:1]
The miR-141-3p may induce oxidative stress in the HepG2 cells. [score:1]
MiR-141-3p also involved in regulating pro-inflammatory cytokines. [score:1]
Above all, the mitochondria-related miR-141-3p might contribute to the mitochondrial dysfunction. [score:1]
These indicated that the miR-141-3p was prone to induce oxidative damage. [score:1]
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7
[+] score: 196
Other miRNAs from this paper: hsa-mir-200b, hsa-mir-200c, hsa-mir-200a
As miR-141 and TM4SF1 were inversely expressed in SP cells, we explored TM4SF1 is a direct target gene of miR-141 and miR-141 could contribute to the self-renewal of esophageal cancer stem-like cells by suppressing TM4SF1. [score:8]
The inverse correlation observed between miR-141 and TM4SF1 in expression suggested that TM4SF1 might be a direct target gene of miR-141. [score:6]
But we found the up-regulation ratio (NSP/SP) of miR-141 expression was dramatically higher than miR-200a. [score:6]
As shown in Figure 5A, we found the expression of miR-141 was significantly down-regulated in tumor than normal tissue of ESCC. [score:6]
Then, we found protein expression levels of TM4SF1 were significantly down-regulated in lenti-miR-141 cells (Figure 4C). [score:6]
Concurrently, we found miR-141 expression was down-regulated in SP cells by real-time PCR (Figure 1D). [score:6]
Thus, our results provide compelling evidence that miR-141 and TM4SF1 could be a potential target of the eliminating cancer stem-like cells in ESCC and might promote the development of new therapeutic strategies and efficient drugs to target ESCC stem-like cells. [score:6]
We found that the expression of MMP-2, MMP-9 and VEGF was decreased after miR-141 overexpressed (Figure 5E). [score:5]
These results indicated that TM4SF1 functioned as a stem renewal factor to be a key regulator factor in the maintenance of cancer stem-like cells and miR-141 regulated the esophageal cancer stem-like cells by suppressing TM4SF1. [score:5]
These results indicated that overexpression of miR-141 in ESCC cells inhibits the carcinogenicity both in vitro and in vivo. [score:5]
Therefore, we used Target Scan 6.0 to predict targets of miR-141 and found that the 3′UTR of TM4SF1 mRNA that matched perfectly to miR-141's 5′ seed sequence. [score:5]
As shown in Figure 6B, ecotopic expression of TM4SF1 in lenti-miR-141 cells was successfully restored TM4SF1 protein expression. [score:5]
The downregulation of miR-141 suggests that normal and breast cancer stem cells share common molecular mechanisms that regulate stem cell functions such as self-renewal, proliferation and EMT [33]. [score:5]
As we found that the expression of miR-141 was down regulated in SP cells, the results suggested that miR-141 might be involved in regulating esophageal cancer stem-like cells. [score:5]
To investigate the critical role of miR-141-TM4SF1 regulation in esophageal cancer stem-like cells in detail, we transfected pENTER-TM4SF1 plasmid and miR-141 inhibitor into the lenti-miR-141 cells to rescue the TM4SF1 expression. [score:4]
In summary, we demonstrated that TM4SF1 was a direct target of miR-141. [score:4]
These results suggested that miR-141 directly targets TM4SF1 via the binding site in its 3′UTR region. [score:4]
TM4SF1 is a direct target of miR-141. [score:4]
Our results indicated TM4SF1 was a direct target gene of miR-141. [score:4]
This result indicated that overexpression of miR-141 could effective regulate the SP phenotype of KYSE150 and KYSE180 cells. [score:4]
The effect of miR-141 overexpression on esophageal cancer stem-like cells. [score:3]
The results showed that the percentage of cells in the SP fraction of miR-141 overexpressed cells was significantly lower than that of its parental cells or lenti-miR-NC cells (Figure 5B). [score:3]
SP analysis indicated that the SP fraction was increased after TM4SF1 overexpression and miR-141 ablated in lenti-miR-141 cells (Figure 6A). [score:3]
However, the expression pattern of miR-141 and its role in ESCC and cancer stem-like of ESCC are poorly understood. [score:3]
A. An miR-141 target site resides at +157 to +163 of the TM4SF1 3′UTR and is highly conserved in different species. [score:3]
TM4SF1 and miR-141 are inversely expressed in esophageal cancer stem-like cells. [score:3]
MiR-141 regulates the esophageal cancer stem-like cells by suppressing TM4SF1. [score:3]
Figure 4 A. An miR-141 target site resides at +157 to +163 of the TM4SF1 3′UTR and is highly conserved in different species. [score:3]
B. After infection of cells with indicated lentivirus, miR-141 expression level was measured by real-time PCR and C. the expression of TM4SF1 mesured by Western blot after KYSE150 and KYSE180 cells infection with lentivirus. [score:3]
We overexpressed miR-141 in KYSE150 and KYSE180 cells using lentivirus -mediated transduction. [score:3]
E. Luciferase acitivity assay demonstrates a direct targeting of the 3′UTR of TM4SF1 by miR-141. [score:3]
The expression of miR-141 in human ESCC. [score:3]
Comparing the sequence for interspecies homology, we found the miR-141 target sequence of TM4SF1 3′UTR is highly conserved among different species. [score:3]
We also transfeced KYSE150 and KYSE180 with miR-141 mimics which overexpress miR-141. [score:3]
And the expression of miR-141 was also higher than miR-200a in KYSE150 and KYSE180 cells. [score:3]
MiR-141 is a member of the miR-200 family, and is reported to be the potential biomarker of various diseases, including hepatocellular carcinoma [40], colorectal cancer [41]. [score:3]
As these cells did not differ in their growth rate (Supplementary Figure 3), lenti-miR-141 cells were less resistant to cisplatin suggested that overexpression of miR-141 in ESCC cells affected their chemotherapeutic drug resistance. [score:3]
Previously, the result from gene-array demonstrates that TM4SF1 and miR-141 were inversely expressed in SP and none-SP cells. [score:3]
The expression of TM4SF1 and miR-141 in esophageal cancer stem-like cells. [score:3]
MiR-141 suppresses migration and invasion in ESCC cells. [score:2]
MiR-141 inhibits the chemotherapeutic resistant ability of esophageal cancer stem-like cells. [score:2]
However, the role of miR-141 in the development of ESCC remains unknown. [score:2]
MiR-141 is a member of the miR-200 family, and is reported to be up or down regulated in many type of cancers [23– 33]. [score:2]
The results showed that overexpression of miR-141 significantly weaken migration and invasion compared with control cells (Figure 5D). [score:2]
These results support the notion that miR-141 regulates TM4SF1 plays an important role in ESCC cells migration and invasion. [score:2]
MiR-141 inhibits clonogencity and tumorigenic ability of ESCC cells. [score:2]
Regulation of TM4SF1 by miR-141 played an important role in controlling the cell proliferation and self-renewal of esophageal cancer stem-like cells. [score:2]
Compared with control cells, miR-141 expression was obviously increased in lenti-miR-141 cells (Figure 4B). [score:2]
In previous study, we sorted SP and NSP cells and used gene microarray to indentify stem cell-related genes and miRNAs which were including TM4SF1 and miR-141. [score:1]
In KYSE180 cells, the IC50 values were 2.199 for KYSE180, 2.297 for lenti-miR-NCand 1.041 for lenti-miR-141. [score:1]
D. Diagram of luciferase reporter plasmids: plasmid with TM4SF1 3′UTR insert (pIS0-TM4SF1-3′UTR) and plasmid with a mutant TM4SF1 3′UTR (pIS0-TM4SF1-3′UTRmut) that carried a substitution of seven nucleotides within the miR-141 binding site. [score:1]
To determine specifically whether miR-141 represses proliferative potential of ESCC cells, we tested the tumorigenic ability of these cells both in vitro and in vivo. [score:1]
This result suggested that miR-141 may play an important role in ESCC. [score:1]
A. SP analysis of cells after transfection or RNA interference of KYSE150-Lenti-miR-141 and KYSE180-Lenti-miR-141 cells. [score:1]
After exposure to cisplatin, the viability of KYSE150 or lenti-miR-NC cells were markedly higher than that of lenti-miR-141 cells (Figure 5C). [score:1]
Fold changes in TM4SF1 and miR-141 expression were calculated using the 2-ΔΔCt method [42]. [score:1]
B, C. In SP and non-SP cells of KYSE150 and KYSE180 cell lines, TM4SF1 expression level was measured by Western blot and real-time PCR, and D. miR-141 expression level was measured by real-time PCR. [score:1]
The data presented here, coupled with those from our earlier report [11– 13], demonstrate TM4SF1 and miR-141 could be a potential marker of cancer stem-like cells of ESCC. [score:1]
It is indicated that miR-141 may play a more important role than miR-200a in SP cells of ESCC. [score:1]
Shown in Figure 4A is the miR-141 binding site at +157 to +163 nucleotides of TM4SF1 3′UTR. [score:1]
Figure 6 A. SP analysis of cells after transfection or RNA interference of KYSE150-Lenti-miR-141 and KYSE180-Lenti-miR-141 cells. [score:1]
G. Tumor weights of KYSE150 cells and its infection cells (lenti-miR-NC and lenti-miR-141 cells) were plotted. [score:1]
MiR-141 regulates the SP phenotype. [score:1]
These results demonstrated that TM4SF1 and miR-141 may play an important role in esophageal cancer stem-like cells. [score:1]
TM4SF1 and miR-141 together played important roles in maintaining the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells. [score:1]
In KYSE150 cells, the IC50 values were 4.729 for KYSE150, 4.364 for lenti-miR-NC and 1.685 for lenti-miR-141. [score:1]
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[+] score: 175
Since TGF-β2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules, and previous report showed that only seasonal influenza H1N1 (but not the other avian influenza subtypes) could induce a persistent expression of TGF-β2, we speculate that the modulation of TGF-β2 expression by different influenza subtypes via miR-141 might be a critical step for determining the outcome of either normal or excessive inflammation progression. [score:8]
However, the effect of miR-141 on virus infection was not known, except one recent report showing that enterovirus can induce miR-141 and contribute to the shutoff of host protein translation by targeting the translation initiation factor eIF4E [30]. [score:7]
This might be because, by the use of anti-miR miR-141 inhibitor, which decreases the cellular pool of miR-141, the translation control of the TGF-β2 mRNA was subsequently released and caused the TGF-β2 protein to express and accumulate during virus infection. [score:7]
Indeed, upon detecting the TGF-β2 expression at mRNA and protein levels, we found that the altered miR-141 expression would affect the expression of the cytokine- TGF-β2. [score:7]
MiR-141 was also found to be overexpressed in ovarian and colorectal cancers [23, 24] and down-regulated in prostate, hepatocellular, renal cell carcinoma and in gastric cancer tissues [25- 28] raising a controversial issue about the role of miR-141 in cancer progression. [score:6]
The results of this experiment showed that the anti-miR miR-141 inhibitor could cause an increase in TGF-β2 protein expression in H1N1 or H5N1 infected cells, as compared to cells only infected with H1N1 or H5N1 but without anti-miR miR-141 inhibitor treatment (Figure 3). [score:6]
Among the listed profiles of differentially up-regulated miRNA, it was found that miR-141, miR-181c*, miR-210, miR29b, miR-324-5p, and miR-663 were up-regulated (>1.5-fold, p<0.05) at 3-hour post-infection with subtype H5 as compared with non-infected control cells. [score:6]
Interestingly, we demonstrated that miR-141, which was more highly induced by H5N1 than by H1N1 (p < 0.05), had an ability to suppress the expression of a cytokine - transforming growth factor (TGF)-β2. [score:5]
However, it was also observed that when there was an increase in TGF-β2 mRNA level, the corresponding TGF-β2 protein expression level would be increased, except in the case of non-miR-141 -inhibitor treated H5N1 infected cells. [score:5]
However, whether the recovery of TGF-β2 expression by anti-miR miR-141 inhibitor could resolve the hypercytokinemia stage of H5N1 infection needs to be further studied. [score:5]
The functional relevance of changes in miR-141 expression during influenza A virus infection was assessed using miRNA inhibitors. [score:5]
In this over -expression system we could determine that the 3′UTR was the miR-141 target and the decreased TGF-β2 mRNA level might be due to the binding of miR-141 to the 3′UTR of TGF-β2 mRNA which reduced the half-lives of TGF-β2 mRNA. [score:5]
That observation coincides with our results in this study, showing that H1N1 infection induced a little amount of miR-141 expression, while H5N1 infection induced a higher amount of miR-141 expression at the early phase of infection. [score:5]
Furthermore, miR-141 may not only work as translational repressors of target mRNAs, because it was observed that they also caused a decrease in TGF-β2 mRNA levels. [score:5]
Our observation is in line with another study showing that the 3′UTR of TGF-β2 mRNA contained a target site for miR-141/200a and the expression of TGF-β2 was significantly decreased in miR-141/200a transfected cells [22]. [score:5]
We found that TGF-β2 mRNA was suppressed in miR-141 overexpressed cells. [score:5]
Interestingly, one of the target prediction results showed that there was a 3′ untranslated region (UTR) binding site on TGF-β2 for miR-141. [score:5]
With high level of miR-141, the expression of TGF-β would be suppressed from the lung epithelial cells. [score:5]
To validate the in silico findings empirically on the target of miR-141, we checked whether transient-transfection of anti- and pre-mir-141 into NCI-H292 cells resulted in TGF-β2 regulation. [score:4]
For H1N1 infected cells, at 18 and 24-hour post-infection, miR-188-5p, miR-1260, miR-1274a, miR-1274b, miR141, miR183*, miR-18b, miR-19a, miR21*, miR-301a, miR-572, miR-720, and miR-939 were found to be up-regulated (>1.5-fold, p<0.05) (Table 1). [score:4]
Moreover, TGF-β2, which plays an important role in regulating inflammatory processes, was identified as a target of miR-141 binding. [score:4]
It has been reported that miR-141 were markedly downregulated in cells that had undergone epithelial to mesenchymal in response to TGF-β. [score:4]
It was found that six miRNAs (miR-21*, miR-100*, miR-141, miR-1274a, miR-1274b and miR-574-3p) were initially up-regulated at 3 hours post-infection. [score:4]
Furthermore, at 18, and 24-hour post-infection, miR-1260, miR-1274a, miR-1274b, miR-141, miR-18b, miR-21*, miR-720, miR-100*, miR-1260, miR1280, and miR21* were found to be down-regulated (>3-fold, p<0.05) in H5N1 infected cells. [score:4]
Therefore, the downregulation of TGF-β2 protein by miR-141 may be an important step in the excessive inflammation progression during influenza A virus infection, particularly in H5N1 infection. [score:4]
In addition, evidence suggests that influenza A virus infection reduces or promotes the expression of the host miR-141 in a time dependent manner. [score:3]
Chemically modified, single stranded nucleic acids anti-miR miR-141 inhibitor and negative control were transfected into H292 cells for 24 hours. [score:3]
We had previously reported that TGF-β2 was an important cytokine involved in the inflammatory response of avian influenza A virus infection [21] and, together with the results showing that the expression of miR-141 was altered during the time course of influenza A virus infection, we selected miR-141 for further functional analysis in this study. [score:3]
NCI-H292 cells with or without treatment of miR-141 inhibitor, were infected with influenza A virus subtypes: H1N1/2002 or H5N1/2004 viruses at m. o. i. = 1, respectively for 24 hours. [score:3]
In our study, we found that the expression of miR-141 was affected by influenza A virus infection. [score:3]
Effect of inhibition of miR-141 in influenza A virus infection. [score:3]
Reverse transfection of a mimic or an inhibitor of miR-141. [score:3]
As a consequence of the higher amount of miR-141 in H5N1 infection, TGF-β2 expression might be more greatly reduced than that in H1N1 infection. [score:3]
We found that miR-21*, miR-100*, miR-141, miR-574-3p, miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection. [score:3]
Moreover, miR-100*, miR-21*, miR-141, miR-1274a and miR1274b were found to be down-regulated (>3-fold, p<0.05) in infection with subtype H5, particularly at 18 or 24 hours post-infection as compared with non-infected control cells. [score:3]
MiR-141 represses the expression of TGF-β2 mRNA. [score:2]
Figure 2 The TGF-β2 3′UTR is regulated by miR-141. [score:2]
However, our findings show that, during highly pathogenic H5N1 avian virus infection, miR-141 would be induced shortly after infection. [score:1]
Literature search on the background of miR-141 confirmed that miR-141 is a member of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429). [score:1]
The miR-141 sequence is: 3′- GGUAGAAAUGGUCU GUCACAAU - 5′, while that of TGF-β2 3′UTR is: 5′-AGAGCCUUGGUUCAU CAGUGUUA-3′. [score:1]
We identified that miR-141 was induced at early time points upon influenza A virus infection. [score:1]
After the cells were pre -treated with anti-miR miR-141 for 24 hours, they were then infected with H1N1 or H5N1, respectively. [score:1]
After the infection processes, anti-miR miR-141 was transfected again into the virus infected cells and incubated for another 24 hours. [score:1]
Previous studies of miR-141 were mainly on its role in cancer. [score:1]
At this time point, only miR-141 was found to be slightly induced in subtype H1 infected cells. [score:1]
As a result, influenza A virus infection, in particular highly pathogenic H5N1, could affect the inflammatory processes via miR-141 induction. [score:1]
This might be explained by the fact that TGF-β2 mRNA degradation induced by miR-141 might be much faster than that of the corresponding protein degradation. [score:1]
NCI-H292 cells were transfected with pre-miR-141 and negative control, respectively. [score:1]
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[+] score: 140
To test whether gain in regulatory microRNAs in undifferentiated BeWo cells, where the expression of the microRNAs is relatively low, lead to change in TTR expression, mature miR-200a-3p or miR-141-3p mimics were transfected into BeWo cells in the absence or presence of the respective inhibitors. [score:8]
Figure 4Overexpression and inhibition of miR-200a-3p and miR-141-3p regulate TTR and its function in human trophoblast cells. [score:6]
In summary, we identified TTR as a direct target of miR-141-3p or miR-200a-3p and demonstrated that TTR and these microRNAs are reciprocally expressed during human trophoblast differentiation. [score:6]
Successful reversal of this suppression phenomenon was observed with the addition of inhibitors for miR-200a-3p and miR-141-3p along with the respective mimics (Fig.   2b and d). [score:5]
Significant up-regulation of both miR-141-3p and miR-200a-3p levels was observed along with TTR down regulation in differentiating human trophoblast cells. [score:5]
Over expression of either miR-200a-3p or miR-141-3p using mimics in undifferentiated BeWo cells led to reduced expression of TTR transcript. [score:5]
Our data revealed that overexpression of miR-200a-3p or miR-141-3p repressed the expression of TTR in human trophoblast cells. [score:5]
These data are rather intriguing since miR-141-3p emerges as a central regulator of various genes pivotal for proper embryonic development and can be used as a potential biomarker as well as therapeutic target to combat IUGR. [score:5]
Upregulation of this microRNA was also found in placental tissue from FGR patients where miR-141 was found to down regulate E2F3 and PLAG1 [44]. [score:5]
Figure 2MiR-200a-3p and miR-141-3p directly target TTR 3′-UTR. [score:4]
Ospina-Prieto S MicroRNA-141 is upregulated in preeclamptic placentae and regulates trophoblast invasion and intercellular communicationTransl. [score:4]
In agreement with these data, miR-141-3p was found to be up-regulated in labyrinth zone of IUGR rat placenta. [score:4]
Tang Q miR-141 contributes to fetal growth restriction by regulating PLAG1 expressionPLoS ONE. [score:4]
Our finding that miR-141-3p and miR-200a-3p are involved in the regulation of TTR during trophoblast differentiation provides yet another mechanism by which microRNA adds a complementary layer of control at the post-transcriptional level to developmentally indispensible genes known to be transcriptionally regulated. [score:4]
These data strongly suggest that miR-200a-3p and miR-141-3p may regulate the expression of TTR and consequently TTR -mediated delivery of thyroxin hormone in placental trophoblast cells. [score:4]
The putative binding sites for miR-141-3p and miR-200a-3p on 3′-UTRs of human and rat TTR were identified using the TargetScan mouse 6.0, PicTar, microRNA. [score:3]
In line with our previous results, down regulation of TTR mRNA and protein upon differentiation was associated with significant up regulation of both miR200a-3p and miR-141-3p (Fig.   3f). [score:3]
Similarly microRNA inhibitors for miR-141-3p or miR-200a-3p (Ambion, USA) were transfected at a final concentration of 200 nM to prove the specificity of the microRNA action. [score:3]
Recent studies reported that miR-141-3p, belonging to the miR-200 cluster, is overexpressed in IUGR as well as in preeclamptic placentas 42– 44. [score:3]
To validate whether TTR mRNA is a direct target of miR-200a-3p and miR-141-3p, dual luciferase reporter assay was performed in HEK293 cells. [score:3]
Our study on conserved microRNAs as plausible regulators of TTR biogenesis led to identification of two microRNAs, miR-200a-3p and miR-141-3p that directly bind to the 3′-UTR of TTR. [score:3]
Figure 3Differentiation of human trophoblast cells (BeWo) is associated with reciprocal expression of hTTR and miR-200a-3p, miR-141-3p. [score:3]
It was further demonstrated by our group that miR-141-3p regulates IGF2 during mouse placental development [48]. [score:3]
MiR-141-3p is highly expressed with concurrent down regulation of TTR in human IUGR fetal placenta. [score:3]
Since TTR biogenesis by placental trophoblast cells is crucial for proper fetal development, our results on miR-141-3p and miR-200a-3p in regulating T [4] uptake by human trophoblast cells led to next set of experiments using IUGR rat mo del as well as in human IUGR placentas. [score:3]
Recent reports have shown that, miR-141 is secreted from placental trophoblast and is up regulated in the third trimester (29–40 weeks) of pregnancy, but its expression is increased abnormally in preeclamptic placentas when compared with normal placentas 42, 43. [score:3]
Saha S Choudhury J Ain R MicroRNA-141-3p and miR-200a-3p regulate insulin-like growth factor 2 during mouse placental developmentMol. [score:3]
These data indicate that miR141-3p and miR-200a-3p might play important roles in regulating TTR during normal placental development. [score:3]
In brief, BeWo cells were transfected with miR-141-3p or miR-200a-3p mimic alone or mimic plus inhibitors as described above. [score:3]
Figure 5Induction of IUGR during pregnancy in rats impacts TTR and the regulatory microRNAs, miR-200a-3p and miR-141-3p. [score:2]
Mutated version of hTTR 3′UTR (5′-CGGTGCT-3′) were generated by introducing two point mutations in the seed region (5′-CAGTGTT-3′) of miR-141-3p and miR-200a-3p. [score:2]
Interestingly, our data highlight that in human IUGR placenta the regulation of TTR by miR-141-3p and not miR-200a-3p is physiologically relevant like that in rat. [score:2]
MiR-141-3p or miR-200a-3p can regulate endogenous TTR protein levels as well as thyroxin uptake by human trophoblast cells. [score:2]
Cells were transfected with microRNA mimics for miR-141-3p or miR-200a-3p (Ambion, USA) individually at a final concentration of 200 nM (titrated for maximum down regulation of TTR prior to this experiment, data not shown) using Lipofectamine RNAiMAX (Invitrogen, USA) as per manufacturer’s instructions. [score:2]
On the contrary, under pathophysiological conditions, such as, IUGR, only miR-141-3p is relevant and it regulates TTR levels both in rats and human during IUGR. [score:2]
This data clearly indicates that both miR-200a-3p and miR-141-3p have the ability to regulate endogenous TTR protein levels in human trophoblast cells. [score:2]
Leading on from this, we tested the role of miR-141-3p and miR-200a-3p in term placenta from human control and IUGR pregnancies. [score:1]
Figure 1Cellular source of TTR in developing rat placenta and miR-200a-3p, miR-141-3p binding sites on 3′-UTR of TTR mRNA (a) Quantitative real time PCR analysis of TTR mRNA from rat placental samples at different days of gestation. [score:1]
Both miR-141-3p and miR-200a-3p share a common microRNA response element (MRE) on the 3′UTR of TTR transcript, which is highly conserved across species including humans (Fig.   1c). [score:1]
As expected, miR-141-3p was significantly up regulated in the labyrinth zone of the IUGR placentae as compared to control. [score:1]
Using various bioinformatic software, binding sites of two microRNAs, miR-141-3p and miR-200a-3p were identified to be present in the 3′-UTR of human TTR and were found to be conserved across species. [score:1]
These trophoblast cells can be used as an ex vivo mo del system for studying the effects of miR-141-3p and miR-200a-3p on endogenous TTR during trophoblast differentiation. [score:1]
In the first construct 14–263 nucleotide of 3′UTR of TTR containing the putative MRE for miR-200a-3p and miR-141-3p (5′-CAGTGTT-3′) was cloned downstream of the firefly luciferease reporter in the pmirGLO plasmid and was denoted as ‘wild type’. [score:1]
They also have shown that in IUGR patients, elevated concentration of miR-141-3p can repress PLAG1 at both transcriptional and posttranscriptional levels. [score:1]
Output from various microRNA prediction tools has been revealed that two members of miR-200 family, miR-200a-3p and miR-141-3p have conserved binding sites on the 3′UTR of TTR mRNA. [score:1]
These results along with our data indicate that miR-141-3p might function differently in different cellular and physiological context. [score:1]
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[+] score: 135
Subsequent qRT-PCR analysis further showed that overexpression of microRNA-141 in SW480 and SW620 cells decreased the expression of CTNNA1 mRNA than the controls, whereas the inhibitory effect of microRNA-141 on CTNNA1 expression was completely abolished by the introduction of CTNNAP1 and knockdown of microRNA-141 (Figure 2F). [score:10]
Figure 4Schematic overview of pseudogene CTNNAP1 regulatory network in CRC pathogenesisDownregulation of pseudogene CTNNAP1 downregulated its cognate gene CTNNA1 mRNA level via mediating microRNA-141 repression activity, thereby conferred a malignant phenotype to colorectal cancer cells. [score:8]
MicroRNA-141 inhibited pseudogene CTNNAP1 and its cognate gene CTNNA1 in CRCPseudogenes are believed quite recently to play important roles in varies of diseases via competing for the binding of common microRNAs molecule with their parental genes, thereby liberating mRNA transcripts expression of microRNAs targets [17, 18]. [score:8]
Figure 2MicroRNA-141 inhibits the expression levels of pseudogene CTNNAP1 and its cognate gene CTNNA1 in CRC A. The expression of microRNA-141 in CRC tissues and paired nontumor tissues. [score:7]
Downregulation of pseudogene CTNNAP1 downregulated its cognate gene CTNNA1 mRNA level via mediating microRNA-141 repression activity, thereby conferred a malignant phenotype to colorectal cancer cells. [score:7]
Finally, the mechanisms accounting for the correlation expression of CTNNAP1 and CTNNAP1 showed that CTNNAP1 behaved as a ceRNA to sustain the expression of its parental gene CTNNA1 transcript from being inhibited by microRNA-141. [score:7]
Expression of CTNNAP1 and knockdown of microRNA-141 partially abrogated the inhibitory effect of microRNA-141 (Figure 2D and 2E). [score:6]
The expression of microRNA-141 is significantly up-regulated in cancer tissues than normal controls. [score:6]
F. After transfection microRNA-141 mimics with plasmid harboring full length CTNNAP1 or microRNA-141 inhibitor, the effect of microRNA-141 on CTNNA1 mRNA level or CTNNAP1 in antagonizing microRNA-141 -mediated suppression of CTNNA1 mRNA level was examined by qRT-PCR. [score:5]
In addition, qRT-PCR analysis showed that microRNA-141 expression was inversely correlated with CTNNA1 and CTNNAP1 expression. [score:5]
In the current study, we demonstrated for the first time that lower expression of pseudogene CTNNAP1 resulted in CTNNA1 mRNA level suppression by microRNA-141, and conferred a malignant phenotype to colorectal cancer cells lines (Figure 4). [score:5]
And in the present study, we showed that CTNNAP1 and CTNNA1 are the major direct target genes of microRNA-141, though the results are not completely consistent with previous studies. [score:4]
Among these microRNAs, microRNA-141 was found to be up-regulated in the same CRC tissues in comparison with matched normal tissues (Figure 2A). [score:4]
As we expected, luciferase activity of reporter plasmids containing the mutant CTNNA1 3′-UTR was not affected in cells which were transfected microRNA-141 mimics with inhibitors or plasmid encoding CTNNAP1 in comparison with controls (Figure 2D and 2E), suggesting a direct interactions between microRNA-141 and its putative recognition sites. [score:4]
MicroRNA-141 inhibits the expression levels of pseudogene CTNNAP1 and its cognate gene CTNNA1 in CRC. [score:4]
Furthermore, gain-of-function assays were further explored that pseudogene CTNNAP1 could act as a ceRNA to increase CTNNA1 gene expression through competition for microRNA-141, subsequently inhibiting cell proliferation and tumor growth. [score:4]
B. Negative correlation between CTNNAP1, CTNNA1 expression and microRNA-141 level in tissues of 56 CRC patients (P<0.001, R [2]=0.3166 between CTNNAP1 and microRNA-141; P<0.001, R [2]=0.3038 between CTNNA1 and microRNA-141). [score:3]
In summary, the present study has suggested pseudogene CTNNAP1 is a potential tumor suppressor participating in CRC pathogenesis by competing with the parent gene CTNNA1 for microRNA-141. [score:3]
Together, these data indicate that pseudogene CTNNAP1 can function as microRNA-141 decoy, thereby increasing its cognate gene CTNNA1 expression by sequestering microRNAs. [score:3]
D. and E. Luciferase reporter containing the wild type CTNNA1 3′-UTR or mutant CTNNA1 3′-UTR were transfected plasmid harboring full length CTNNAP1 (pcDNA3.1- CTNNAP1) or microRNA-141 inhibitors in combination with microRNA-141 mimics. [score:3]
These results indicate that microRNA-141 could suppress CTNNAP1 and its cognate gene CTNNA1. [score:3]
In addition, correlation analyses revealed that microRNA-141 significantly correlated with the expression of CTNNAP1 and CTNNA1 in the CRC tissues (P<0.001, R [2]=0.317 for CTNNAP1; P<0.001, R [2]=0.304 for CTNNA1) (Figure 2B). [score:3]
Furthermore, reporter plasmids containing the wild type 3′-UTR of CTNNA1 were subsequently transfected plasmid encoding CTNNAP1 (pcDNA3.1- CTNNAP1) or microRNA-141 inhibitors along with microRNAs mimics. [score:3]
In recent years, it has been discovered that microRNA-141 can influence DLC1 and SIP1 genes to participate in human diseases, including CRC [35– 37]. [score:3]
A. The expression of microRNA-141 in CRC tissues and paired nontumor tissues. [score:3]
Furthermore, the half-life of CTNNAP1 and CTNNA1 regulated by microRNA-141 was shorter in CRC cells (t [1/2]=2h for CTNNAP1 and t [1/2]=4h for CTNNA1 in SW480 cells; t [1/2]=3h for CTNNAP1 and t [1/2]=2h for CTNNA1 in SW620 cells) after actinomycin D treatment than in control cells (t [1/2]=5h for CTNNAP1 and t [1/2]=6h for CTNNA1 in SW480 cells; t [1/2]=4h for CTNNAP1 and t [1/2]=5h for CTNNA1 in SW620 cells). [score:2]
MicroRNA-141 inhibited pseudogene CTNNAP1 and its cognate gene CTNNA1 in CRC. [score:2]
This study showed the first evidence for the cross-talk between CTNNAP1 and CTNNA1 via competing for microRNA-141, shedding a better understanding of molecular etiology of CRC. [score:1]
Reporter plasmids containing 3′-UTR of CTNNA1 (RLuc- CTNNA1-WT or RLuc- CTNNA1-MU) (Figure 2C), which contains wild-type or mutant microRNA-141 binding sites transfected with microRNAs mimics or negative controls into CRC cells. [score:1]
As showed in Figure 2G and 2H, the transcript levels of the CTNNAP1 and CTNNA1 was declined in CRC cells after RNA synthesis was blocked with Actinomycin D in the presence of microRNA-141. [score:1]
Twenty-four hours after cells were transfected with 40 pmol microRNA-141 mimics (Shanghai GenePharma Co. [score:1]
The wild-type CTNNA1 3′-UTR containing the microRNA-141 recognition site (CTNNA1 3′-UTR-WT) or mutant CTNNA1 3′-UTR harboring mutated microRNA-141 binding site (CTNNA1 3′-UTR-MU) was cloned downstream of the luciferase gene. [score:1]
Notably, microRNA-141 had been reported to promote cell growth, cell cycle progression and tumor invasion in CRC [19]. [score:1]
The half-life of CTNNAP1 and CTNNA1 decreased by microRNA-141. [score:1]
Considering the potential binding sites for microRNA-141 in CTNNAP1 and CTNNA1 genes (Supplementary Table S1) as well as the coordinated expression levels of CTNNAP1, CTNNA1 and microRNA-141, we performed dual luciferase reporter assays to investigate whether CTNNAP1 and CTNNA1 were regulated by microRNA-141. [score:1]
Based on the bioinformatics tools and the reference [11], 4 potential microRNAs binding sites scattered the CTNNAP1 transcript as well as the sequence of CTNNA1 3′-UTR (microRNA-141, microRNA-18b, microRNA-33a and microRNA-9). [score:1]
C. Schematic outlining of human CTNNA1 3′-UTR, and the position of the predicted microRNA-141 binding sites on CTNNA1 3′-UTR sequence. [score:1]
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11
[+] score: 134
In this study, we show that the epigenetic state is closely linked to normal cell type specific expression of miR-200c and miR-141, and this epigenetic state is dysregulated in carcinoma cells, where loss of miR200c/141 expression is linked to aberrant DNA methylation and histone modifications. [score:6]
In all cases, miR-200c and miR-141 were highly expressed in epithelial cells, but were not expressed in fibroblasts. [score:5]
The PC3 cells that have lost miR-200c and miR-141 expression, display an aberrantly methylated CpG island and a mesenchymal phenotype, whereas LnCaP and Du145 retain miR-200c and miR-141 expression and an epithelial phenotype [11], [30]. [score:5]
miR-200c and miR-141 expression is lost in different types of cancer cells [5], [11], [20], [21], and we sought to determine if this loss of expression was linked to epigenetic changes in the miR-200c/miR-141 CpG island. [score:5]
We show two prostate cancer cell lines (PC3 and PC3 B1) where loss of miR-200c and miR-141 expression is linked with aberrant DNA methylation of the mir-200c/141 CpG island (Figure 3B; Figure S3), and two prostate cancer cell lines (LNCaP and DU145) that retain miR-200c/miR-141 expression and an unmethylated mir-200c/141 CpG island. [score:5]
Mamm Genome 20 Du Y Xu Y Ding L Yao H Yu H 2009 Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. [score:4]
In addition to the role of miR-200c and miR-141 in the phenotypic conversion of normal cells, dysregulation of normal patterns of miR-200c expression occurs in multiple types of cancer cells and is linked to tumor progression [2], [6], [12], [13], [14], [15]. [score:4]
Dysregulation of miR-200c and miR-141 occurs in multiple cancer types [5], [11], [20], [21], [23], [24], [25], [26], and this dysregulation involves a compromise of the epigenetic state of the CpG island associated with miR-200c and miR141. [score:3]
Figure S4 miR-141 expression in cancer cell lines is reactivated by. [score:3]
The miR-200c/miR-141 -negative breast cancer cell lines MDA-MB-231 and BT549 and prostate cancer cell line PC3 were treated with 3 µM 5-AdC for 96 h and miR-200c/141 expression was assessed by real-time PCR. [score:3]
To demonstrate the functional significance of the epigenetic state of the miR-200c/mir-141 CpG island in cancer cells, we exposed cancer cells to the epigenetic modifier and DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-AdC). [score:3]
Figure S1 Real-time PCR assessment of miR-141 expression in normal cell types. [score:3]
A CpG island near the predicted mir-200c/mir-141 transcription start site shows a striking correlation between miR-200c and miR-141 expression and DNA methylation in both normal and cancer cells, as determined by MassARRAY technology. [score:3]
The left panel shows the expression of miR-141 in eleven human breast cancer cell lines. [score:3]
Epigenetic mechanisms participate in the control of miR-200c and miR-141 expression in both normal and cancer cells. [score:3]
The CpG island is unmethylated in human miR-200/miR-141 expressing epithelial cells and in miR-200c/miR-141 positive tumor cells. [score:3]
Seven of the breast cancer cell lines tested express miR-200c and miR-141 and each has an unmethylated mir-200c CpG island. [score:3]
We report that DNA methylation plays a role in the normal cell type-specific expression of miR-200c and miR-141 and this role appears evolutionarily conserved, since similar results were obtained in mouse. [score:3]
We analyzed 11 breast cancer cell lines, and in each case, miR-200c and miR-141 expression was closely linked to the DNA methylation state of the CpG island (Figure 3A; Figure S3). [score:3]
A similar reactivation of miR-141 expression (p-value<0.01) was also observed in these cancer cell lines after 5-AdC treatment (Figure S4). [score:3]
The inverse correlation between miRNA expression and DNA methylation extends to other miR-200c/miR-141 -positive/negative pairs of normal cells, such as prostate epithelial cells and skin keratinocytes, and their mesenchymal cell type counterparts, prostate and skin fibroblasts. [score:3]
Figure S3 Real-time PCR assessment of miR-141 expression in breast and prostate cancer cell lines. [score:3]
These data suggest that epigenetic mechanisms participate in the inappropriate repression of miR-200c/miR-141 expression in cancer cells. [score:3]
Real time PCR analysis of miR-141 expression in these samples is provided in Figure S1. [score:3]
We corroborated the expression of miR-200c and miR-141 in the same set of normal mammary samples by real-time PCR, and then expanded these results to pairs of epithelial cells and fibroblasts from prostate and skin, as well (Figure 1B; Figure S1). [score:3]
Since miR-200c and miR141 play an important role in EMT and therefore cell identity, disruption of mechanisms that govern cell type specific DNA methylation patterns during carcinogenesis could likely effect expression of miR-200c and miR141 and provide phenotypic plasticity to cancer cells. [score:3]
The left panel shows the expression of miR-141 in three isogenic pairs of mammary epithelial cells (HMEC) and mammary fibroblasts (FB). [score:3]
The right panel shows the expression of miR-141 in human prostate epithelial cells (PREC), prostate stromal fibroblasts (PSF), human skin keratinocytes (Kcytes) and skin fibroblasts (HFF). [score:3]
It is apparent from the small RNA library sequencing data (Figure 1A) that the most highly expressed members of the miR-200 family in HMEC are miR-200c and miR-141. [score:3]
All four of the breast cancer cell lines that lost miR-200c and miR-141 expression have an aberrantly methylated mir-200c/141 CpG island, and each of these cell lines displays a mesenchymal phenotype [11], [29]. [score:3]
The right panel shows the expression of miR-141 in four human prostate cancer cell lines. [score:3]
In contrast, those breast cancer cell lines that express miR-200c and miR-141 and have an unmethylated CpG island display an epithelial phenotype [11], [29]. [score:3]
The epigenetic modifier drug, 5-aza-2′-deoxycytidine, reactivates miR-200c/miR-141 expression showing that epigenetic mechanisms play a functional role in their transcriptional control. [score:3]
The other four breast cancer cell lines tested do not express miR-200c and miR-141 and exhibit a densely methylated mir-200c CpG island. [score:3]
miR-200c and miR-141 are members of the miR-200 family and are important regulators of the epithelial to mesenchymal transition (EMT) [5], [9], [10], [11]. [score:2]
The whole genomic cluster containing mir-200c and mir-141 is well conserved between the human and mouse genome. [score:1]
The regions encoding the hairpins of mir-200c and mir-141 and the putative transcription start (TSS) inferred from the mouse EST track displayed on the UCSC genome browser are shown, and each circle on this track represents the location of a CpG dinucleotide. [score:1]
Results show that the CpG sites are unmethylated in three separate strains of miR-200c/miR-141 -positive HMEC. [score:1]
The CpG island of mir-200c/141 in the three different strains of miR-200c/miR-141 -positive HMEC exists in a transcriptionally competent state; it is enriched for the transcriptionally permissive modifications of histone H3 acetylation (H3Ac) and lysine 4 trimethylation (H3TriMeK4), while the transcriptionally repressive histone mark of histone H3 lysine 9 dimethylation (H3DiMeK9) is underrepresented (Figure 5). [score:1]
In contrast, in the isogenic miR-200c/miR-141 -negative mammary fibroblasts permissive histone modifications are absent, and the repressive H3 lysine 9 dimethylation mark is present (Figure 5). [score:1]
Figure S4 shows the 5-aza-2′-deoxycytidine -mediated reactivation of miR-141 in the same samples. [score:1]
Together these results indicate that cancer cells derived from normal miR-200c/miR-141 -positive epithelial cells can replicate the cell type-specific DNA methylation pattern of the miR-200c/141 CpG island seen in normal miR-200c/miR-141 -negative cells, and that the aberrant DNA methylation of the miR200c/141 CpG island in these cancer cells is associated with its transcriptional silencing in carcinoma cells. [score:1]
Results suggest that these carcinoma cells may co-opt de novo DNA methylation pathways involved in the epigenetic control of normal cell type-specific genes, such as those that govern the epigenetic state of miR-200c/miR-141. [score:1]
Third, the epigenetic modifier 5-aza-2′-deoxycytidine relieves the repression of miR-200c/miR-141 in cancer cell lines. [score:1]
The regions encoding the mir-200c and mir-141 hairpins and the putative transcription start (TSS) region inferred from the human EST track of the UCSC genome browser are displayed, and each circle on this track represents the position of a CpG dinucleotide. [score:1]
In contrast, all the CpG sites are highly methylated in the isogenic miR-200c/miR-141 -negative fibroblast strains. [score:1]
The CpG island is heavily methylated in human miR-200c/miR-141 negative fibroblasts and miR-200c/miR-141 negative tumor cells. [score:1]
In contrast, repressive H3K9 dimethylation marks are present in normal miR-200c/miR-141 -negative fibroblasts and miR-200c/miR-141 negative cancer cells and the permissive histone modifications are absent. [score:1]
Cells were treated with 3 µM 5-AdC for 96 h. The level of expression of miR-141 was measured by real-time PCR. [score:1]
Thus, the miR-200c cluster CpG island is unmethylated in normal miR-200c/miR-141 -positive epithelial cells, while being densely methylated in the paired normal miR-200c/miR-141 -negative fibroblasts (Figure 1B, Figure 2B, Figure S2). [score:1]
One cluster resides on human chromosome 1 and encodes miR-200b, miR-200a, and miR-429, while the other cluster is located on human chromosome 12, and encodes miR-200c and miR-141. [score:1]
Enrichment of permissive histone modifications, H3 acetylation and H3K4 trimethylation, is seen in normal miR-200c/miR-141 -positive epithelial cells, as determined by chromatin immunoprecipitation coupled to real-time PCR. [score:1]
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12
[+] score: 131
The results revealed that PQ could inhibit the expression of miR-200a-3p and miR-21, but up-regulated the levels of miR-141-3p and miR-153 in damaged lung tissues; EPCs injection significantly attenuated the PQ induced-up-regulation of miR-141-3p (approximate to 60%), while EPCs had no significant effect on the expression of miR-200a-3p, miR-21 and miR-153 (Fig.   3a). [score:13]
Moreover, miR-141-3p knockdown also reversed the PQ induced -inhibition on Nrf2, Hmox1 and Txnrd1 expression, while si-Notch-1 further considerably reduced the effect of miR-141-3p knockdown on Nrf2, Hmox1 and Txnrd1 expression (Fig.   5e). [score:9]
However, miR-141-3p knockdown via the transfection of miR-141-3p inhibitor reversed the PQ induced -inhibition on Notch-1and Hesr1 expression (Fig.   5d). [score:8]
Meanwhile, the inactivity of Notch signaling inhibited the same effect with miR-141-3p over -expression on inhibiting EPCs remission on PQ -induced ALI. [score:7]
PQ MiR-141-3p over -expression via the transfection of miR-141-3p mimic (Fig.   5a) could inhibit the expression of Notch-1 (to 49% at mRNA level and 55% at protein level) and Hesr1 (to 46% at mRNA level and 48% at protein level) significantly in the pulmonary epithelial cell line MLE-12 (Fig.   5b, c). [score:7]
MiR-141-3p over -expression could inhibit the expression of Notch-1 pathway significantly in the pulmonary epithelial cell line MLE-12. [score:6]
As reported by Shen et al. [14], miR-141-3p could relieve chronic inflammatory pain via down-regulation of downstream target gene HMGB1. [score:6]
EPCs inhibited miR-141-3p expression, and enhanced the levels of Notch-Nrf2 axis in PQ -induced ALI mice. [score:5]
MiR-141-3p knockdown reversed the PQ induced -inhibition on Notch-1 and Hesr1 expression. [score:5]
Notch signaling are Hes (Hairy and enhancer of split) and Hesr (Hes-related, also known as Hey/Herp/Hrt/Gridlock/Chf) family genes [31], and were inhibited that could reserve the reduced the effect of miR-141-3p knockdown on Nrf2 pathway in our study. [score:4]
PQ also caused the dysregulated expression of some miRNAs including miR-200a-3p, miR-21, miR-141-3p and miR-153, and only the level of miR-141-3p was influenced by EPCs. [score:4]
It is no exception that miR-141-3p plays the important roles in many physiological processes and its deregulation was involved in many diseases. [score:4]
MiR-141-3p over -expression also significantly decreased the protein expression of Notch-1and Hesr1 in lung tissues (Fig.   6c). [score:4]
Both miR-141-3p over -expression and si-Notch-1 abolished the protection effect of EPCs on lung injury induced by PQ in vivo. [score:3]
MLE-12 cells co -transfected with miR-141-3p inhibitor and si-Notch-1 or si-control and then treated by PQ. [score:3]
pre-NC According to lung function tests including the lung W/D ratio and Lung injury score, both miR-141-3p over -expression and si-Notch-1 abolished the protection effect of EPCs on lung injury induced by PQ in vivo (Figs.   6a, b; 7a, b, d). [score:3]
EPCs abolished the effect of PQ on the expression of miR-141-3p, Notch-1 and Nrf2. [score:3]
d MLE-12 cells were transfected with miR-141-3p inhibitor or its control (NC) and then treated by PQ. [score:3]
e MLE-12 cells were divided into six groups, which were received diverse treatment: MLE-12 cells cultured in normal condition; MLE-12 cells treated by PQ; MLE-12 cells transfected with miR-141-3p inhibitor or its control (NC) and then treated by PQ. [score:3]
IGF-2 was regulated by miR-141-3p to influence the activation of Akt in the mouse placental development [15]. [score:3]
In addition, it was reported that Notch-1 were the downstream target gene of miR-141-3p in the Ovaries [16]. [score:3]
To assess the effect of miR-141-3p/Notch axis on mice pulmonary epithelial cells, si-Notch-1/si-control, miR-141-3p inhibitor/miR-NC (negative control) synthesized by RiboBio (Guangzhou, China) and Lipofectamine 2000 (Invitrogen, Carlsbad, USA) were attenuated with Opti-MEM, respectively. [score:3]
In addition, over -expression of miR-141-3p could abolish the effect of EPCs on the lung function. [score:3]
a The pulmonary epithelial cell line MLE-12 was transfected with miR-141-3p mimic or its control (pre-NC), and b the mRNA and c protein expressions of Notch-1 and Hesr1 were then determined. [score:3]
a The expressions of miR-200a-3p, miR-21, miR-141-3p and miR-153 in lung tissues were determined using qRT-PCR. [score:3]
PQ regulated Notch-Nrf2 axis through miR-141-3p in vitro. [score:2]
C57BL/6J mice were randomly divided into four groups (n = 10 per group), the PQ group; the PQ + EPCs group; the EPCs group; the PQ + EPCs + pre-NC group; the PQ + EPCs + miR-141-3p mimic group. [score:1]
In this study, we aimed to invatigate the underlying mechanism of EPCs in PQ -induced ALI involving miR-141-3p. [score:1]
In the following experiments, the mice were randomly distributed into four groups: the PQ group (n = 10), the PQ + EPCs group (n = 10), the EPCs group (n = 10), the PQ + EPCs + pre-NC group (mice were received the injection of PQ, and then received EPCs injection and pre-NC after 6 h, n = 10), the PQ + EPCs + miR-141-3p mimic group (mice were received the injection of PQ, and then received EPCs injection and miR-141-3p mimic after 6 h, n = 10). [score:1]
Fig.  5The interaction between miR-141-3p and Notch-1 in pulmonary epithelial cells. [score:1]
The protection effect of EPCs on the PQ induced lung injury was mediated by miR-141-3p-Notch-Nrf2 axis in vivo. [score:1]
In addition to miR-141-3p, the impact of PQ on Notch-Nrf2 axis was also reversed by EPCs. [score:1]
Endothelial progenitor cells could provide therapeutic effect on PQ -induced ALI via miR-141-3p-Notch-Nrf2 Axis. [score:1]
We aimed to invatigate the underlying mechanism of EPCs in PQ -induced ALI involving miR-141-3p. [score:1]
EPC miR-141-3p Notch-Nrf2 axis PQ ALI As the world-wide and nonselective contact quaternary nitrogen herbicide [1], paraquat (1,1-dimethyl-4,4-bipyridilium dichloride, PQ) presents with high toxicity for humans and animals [2, 3]. [score:1]
In summary, EPCs could provide therapeutic effect on PQ -induced ALI via miR-141-3p-Notch-Nrf2 Axis. [score:1]
Hence, we confirmed that EPCs improved ALI via miR-141-3p. [score:1]
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13
[+] score: 113
miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms. [score:8]
Expression of MIR141 in thyroid tissuesA comparison of relative gene expression across the thyroid cohorts identifies an association between MIR141 expression and malignant thyroid phenotypes. [score:7]
TGFBR1 is expressed in cPTC but not in HT thyrocytesA subset of HT and cPTC samples (n = 3/cohort) were assayed for the expression of TGFβ R1, a member of the TGFβ pathway and known target of MIR141 (Braun et al., 2010). [score:6]
Analysis of variance also demonstrates that the follicular variant of PTC displays a statistically significant (p < 0.05) pattern of downregulation of MIR141 expression compared to both control and cPTC samples. [score:5]
A comparison of relative gene expression across the thyroid cohorts identifies an association between MIR141 expression and malignant thyroid phenotypes. [score:5]
The expression of MIR141 is statistically significantly downregulated in HT tissues compared to both control and cPTC tissues. [score:5]
In the present study, an investigation into the expression of MIR141 in a series of archival thyroid malignancies [cPTC, fvPTC, FTC, HT, or control (no evidence of disease or goiter tissues) tissues] was performed, with an aim to elucidating the expression MIR141 across subtypes of follicular thyroid neoplasia. [score:5]
Expression of MIR141 was significantly downregulated (p < 0.05) in HT samples compared to both control and cPTC samples (Figure 2). [score:5]
Thus, the association of MIR141 with the regulation of this pathway may be reflected in its downregulation in HT epithelium. [score:5]
MIR141 expression is upregulated in these cPTC samples compared to the isolated HT thyrocyte samples. [score:5]
Of the 111 samples expressing the endogenous control, 104 samples also expressed MIR141. [score:5]
A subset of HT and cPTC samples (n = 3/cohort) were assayed for the expression of TGFβ R1, a member of the TGFβ pathway and known target of MIR141 (Braun et al., 2010). [score:4]
It has been demonstrated that MIR141 is upregulated in a cell line mo del of ret/PTC-1 associated PTC (Cahill et al., 2006). [score:4]
Multiple members of the TGFβ pathway have been identified to be direct targets of MIR141 (Braun et al., 2010; Senanayake et al., 2012). [score:4]
MIR141 has been confirmed to directly target a number of genes. [score:4]
The MIR200 family, including MIR141, have been demonstrated to directly regulate members of this pathway as part of a regulatory feedback loop. [score:4]
The fvPTC tissues also display a statistically significant downregulation of MIR141 in comparison to both control and cPTC tissues. [score:4]
PTC variant Year of biopsy RET/PTC mutation PTC variant Year of biopsy RET/PTC mutation Classic 1980 Unknown Follicular variant 1986 Negative Classic 1985 Unknown Follicular variant 1987 Unknown Classic 1987 Unknown Follicular variant 1989 Negative Classic 1994 RET/PTC-1 Follicular variant 1991 Negative Classic 1998 Negative Follicular variant 1991 Negative Classic 1998 RET/PTC-1 Follicular variant 1992 RET/PTC-1 Classic 2002 Negative Follicular variant 1992 Unknown Classic 2002 Negative Follicular variant 1992 Unknown Classic 2002 Negative Follicular variant 1992 Negative Classic 2003 Negative Follicular variant 1993 RET/PTC-3 Classic 2004 Negative Follicular variant 1996 Unknown Classic 2004 Negative Follicular variant 2001 Negative Classic 2004 Negative Follicular variant 2003 Negative Classic 2004 Negative Follicular variant 2003 Negative Classic 2004 Negative Follicular variant 2004 Negative Classic 2004 Negative Follicular variant 2004 Negative Classic 2005 Negative Follicular variant 2004 Negative Classic 2005 Negative Follicular variant 2004 Negative Classic 2005 Negative Follicular variant 2005 Negative Classic 2005 Negative Follicular variant 2005 Negative In this study a significantly decreased expression of MIR141 was identified in thyrocytes isolated from HT tissues compared to both control and cPTC samples. [score:4]
Multiple members of the TGFβ pathway, including transforming growth factor, beta receptor 1 (TGFβR1), have been identified to be direct targets of MIR141 (Braun et al., 2010; Senanayake et al., 2012). [score:4]
This cohort of samples expressing both RNU6B and MIR141 consisted of 20 cPTC samples, 20 fvPTC samples, 19 FTC samples, 21 HT samples, and 24 control samples. [score:3]
Expression of MIR141 in thyroid tissues. [score:3]
In conclusion, HT epithelium can be distinguished from neoplastic follicular thyroid epithelium isolated from cPTC and control epithelium based on the relative expression of MIR141. [score:3]
In the current study, we investigated if the pattern of MIR141 expression would translate to clinical specimens. [score:3]
Figure 2Boxplot of relative quantitation (RQ) of change in expression of MIR141 across cohorts of follicular thyroid malignancy. [score:3]
Both TGFβR1 and SMAD2 are negatively regulated by MIR141. [score:2]
This enforces the accuracy of the associations identified between MIR141 and malignant thyroid phenotypes. [score:1]
Real-time PCR was performed according to TaqMan [®] miRNA assays protocol using MIR141-specific or RNU6B-specific inventoried real-time miRNA expression assays. [score:1]
Cahill et al. (2006) identified a miRNA signature profile for a cPTC cell line that displays significant upregulaution of MIR141. [score:1]
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14
[+] score: 94
To affirm miR-141 involvement in paeonol -inhibited cell motility, miR-141 inhibitor transfection of cells reversed paeonol -suppressed cancer migration (Figure 3C,D). [score:7]
We hypothesized miR-141 mediating paeonol -inhibited cancer migration and found that paeonol increased miR-141 expression; transfection with miR-141 inhibitor rescued paeonol-reduced chondrosarcoma metastasis. [score:7]
Up-regulation of miR-141 is thus a novel strategy to suppress tumor motility. [score:6]
Whether paeonol inhibited chondrosarcoma metastasis by up -regulating miR-141 through targeting these common molecules needs further examination. [score:6]
Xu L. Li Q. Xu D. Wang Q. An Y. Du Q. Zhang J. Zhu Y. Miao Y. hsa-miR-141 down-regulates TM4SF1 to inhibit pancreatic cancer cell invasion and migration Int. [score:6]
Paeonol Reduces Motility in Chondrosarcoma Cells by Up-Regulation of miR-141 Expression. [score:6]
Results indicate that paeonol reduces chondrosarcoma metastasis through up-regulation of miR-141 expression. [score:6]
This study showed paeonol inhibiting migration and invasion by human chondrosarcoma cells, as well as up-regulation of miR-141 through PKCδ and c-Src pathways involved in paeonol -mediated effects. [score:6]
miR-141 has been indicated to suppress the migration and invasion of hepatocellular carcinoma cells (HCC) by targeting Tiam1 [24]. [score:5]
We tested paeonol’s reduction of chondrosarcoma metastasis by modulating miR-141 expression to find incubation of chondrosarcoma cells with paeonol raising miR-141 expression in a concentration -dependent manner (Figure 3A,B). [score:5]
Chen B. Huang T. Jiang J. Lv L. Li H. Xia S. miR-141 suppresses proliferation and motility of gastric cancer cells by targeting HDGF Mol. [score:5]
The miR-141 family is well known to inhibit migration and metastasis of human cancer [24, 25, 33], miR-141 as a negative regulator thereof. [score:4]
In addition, up-regulation of the miR-141 through protein kinase C (PKC)δ and c-Src pathways are involved in paeonol-reduced cell motility. [score:4]
The miRNAs have been reported as important regulators of cancer progression and metastasis [23], with miR-141 suggested to inhibit tumor migration and metastasis [24, 25]. [score:4]
We found up-regulation of miR-141 through PKCδ and c-Src pathways involved in paeonol-reduced cancer migration. [score:4]
Data suggest paeonol reducing metastasis by up -regulating miR-141 expression. [score:4]
Paeonol was purchased from Wako Chemicals (Osaka, Japan); rabbit polyclonal antibodies specific for p-PKCδ, PKCδ, p-c-Src, and c-Src from Biotechnology (Santa Cruz, CA, USA); miR-141 inhibitor and Lipofectamine 2000 from Life Technologies (Carlsbad, CA, USA); all other chemicals from Sigma-Aldrich (St. [score:3]
Figure 3Paeonol increases miR-141 expression in chondrosarcoma cells. [score:3]
In gastric cancer cells, miR-141 reduced cell motility by targeting hepatoma-derived growth factor (HDGF) [33]. [score:3]
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15
[+] score: 84
Other miRNAs from this paper: hsa-mir-200b, hsa-mir-200c, hsa-mir-200a, hsa-mir-429
We analyzed tumor progression associated with miR-141 expression by combining disease recurrence, metastasis, and disease death. [score:7]
Included studies in this meta-analysis referred to evaluating miR-200c and miR-141 expression for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS). [score:5]
When different malignant diseases were considered, the result revealed that high miR-141 expression in urogenital system cancers was associated with a poor DFS/PFS (pooled HR = 1.12; 95% CI: 1.04–1.20; P = 0.002) by the fixed-effects mo del (I [2] = 0.0%, P = 0.821). [score:4]
Hence, the prognostic relevance of miR-200c and miR-141 expression in cancer remains controversial. [score:3]
Based on the stratified analysis, we found that detected sample type had a considerable influence on the prognostic role of miR-141 expression. [score:3]
A total of 536 studies were identified after searching in PubMed, Embase, and Web of Science for publications on miR-200c and miR-141 expression associated with cancer prognosis. [score:3]
Stratified analyses provide further confirmation, in both Asians and Caucasians, that no significant association was found between miR-141 expression and cancer overall survival. [score:3]
Since all the eligible studies focusing on miR-141 expression and tumor progression were carried out with Caucasian cases, subtotal analysis conducted by the ethnicity was not performed. [score:3]
The expression levels of miR-200c and miR-141 were dichotomized in all these 23 studies, but the cut-off value was different, with median, mean, and defined level. [score:3]
Furthermore, High miR-141 expression was better at predicting tumor progression than patient survival for malignant tumors. [score:3]
Tumor Progression (DFS/PFS) Associated with miR-141 Expression. [score:3]
Therefore, in this study, we performed a comprehensive meta-analysis to clarify the prognostic value of miR-200c and miR-141 expression in human cancers. [score:3]
Further stratified analyses by detected sample type displayed that high level of miR-141 remained to be a worse prognostic marker in tissue subgroup (pooled HR = 1.12; 95% CI: 1.04–1.20; P = 0.002) by a fixed-effects mo del (I [2] = 0.0%, P = 0.498) but failed to show a significant association between miR-141 expression and tumor progression in serum/plasma (HR = 0.90; 95% CI: 0.44–1.83; P = 0.771) (Figure 5(b)). [score:3]
The survival outcome of cancer associated with miR-200c or miR-141 expression was estimated by using the hazard ratio (HR) and their associated 95% confidence intervals (95% CI) for each study. [score:3]
The expression of miR-200c and miR-141 was measured in collected cancerous tissues in the majority of studies except seven targeted in circulation samples [23– 25, 27, 29, 37, 39], including one researched in cancerous tissues and blood samples meanwhile [29]. [score:3]
In summary, we concluded that miR-200c and miR-141 expression in peripheral blood may be effective predictors for monitoring cancer progression and prognosis in the future. [score:3]
Overall Survival (OS) Associated with miR-141 Expression. [score:3]
The miRNA-200 family consisting of five highly homologous members (miR-200a, miR-200b, miR-200c, miR-429, and miR-141) can be separated into two gene clusters based on the fact that they are expressed from two distinct polycistronic transcripts; the miR-200b/a/429 cluster is located on chromosome 1p36, and the miR-200c/141 cluster is located on chromosome 12p13 [14, 15]. [score:3]
Quantitative real-time polymerase chain reaction (qRT-PCR) assay was wi dely applied to detect the expression level of miR-200c and miR-141 except two studies which used in situ hybridization (ISH) [30, 38]. [score:2]
Meta-analysis of the eligible studies predicted that high level of miR-141 was significantly associated with poor DFS/PFS (pooled HR = 1.11; 95% CI: 1.04–1.20; P = 0.003). [score:1]
High level of miR-141 may be a significant predictor for poor survival and tumor progression in tissues but not in serum/plasma samples. [score:1]
However, further analysis revealed that high level of miR-141 was correlated with a worse DFS/PFS. [score:1]
However, consensus has not been reached to the reliability of miR-200c and miR-141 as prognostic biomarkers in tumors [19– 21]. [score:1]
This meta-analysis indicated that high level of miR-141 did not predict cancer overall survival. [score:1]
However, there was still significant heterogeneity among Asians in some subgroup analyses (OS for miR-200c: I [2] = 85.1%; OS for miR-141: I [2] = 84.9%). [score:1]
Similar kind of considerations held for the subgroup analyses of tumor type for miR-141, since the heterogeneity of OS for digestive system cancers was obvious (I [2] = 85.9%), while no significant heterogeneity was viewed in other cancer types. [score:1]
It has been documented that the capacity of circulating miR-200c and miR-141 indicated the CTCs status, as well as its potential surrogate markers for CTCs and prognostic markers in patients with metastatic breast cancer [57]. [score:1]
Substantial heterogeneity was discovered in tissue subgroup for miR-200c (OS as endpoint, I [2] = 73.5%), as well as tissue subgroup for miR-141 (OS as endpoint, I [2] = 44.7%). [score:1]
Subgroup analyses failed to exhibit a significant association between high level of miR-141 and overall survival in tissue subgroup (pooled HR = 1.00; 95% CI: 0.92–1.09; P = 0.967) by a fixed-effects mo del (I [2] = 44.7%, P = 0.093) but showed that high level of miR-141 in serum/plasma was a significant prediction for poor OS (pooled HR = 4.34; 95% CI: 2.30–8.21; P = 0.000) by a fixed-effects mo del (I [2] = 0.0%, P = 0.714) (Figure 4(b)). [score:1]
Subgroup analysis on the basis of cancer categories revealed that in urogenital system cancers high level of miR-141 was suitable for predicting tumor progression. [score:1]
Owing to the limitation of the number of eligible studies, the sensitivity analysis for miR-141 with DFS/PFS as the endpoint was not performed. [score:1]
In this meta-analysis, heterogeneity was observed in total comparison for overall survival on miR-200c and miR-141, as well as overall comparison for tumor progression on miR-200c. [score:1]
For quantitative analyses, the pooled HRs along with their 95% CIs of all available trials were grouped into OS and DFS/PFS (including DSS for miR-141). [score:1]
In addition, although series of studies have explored the correlation between miR-141 and prognosis of various cancers, no meta-analysis has been published on this topic to summarize the evidence. [score:1]
The following three sets of key words and their combination search terms were simultaneously applied, namely, “miR-200c OR miR-141,” “cancer OR carcinoma OR tumor OR malignant neoplasm,” and “survival OR prognosis OR outcome. [score:1]
The main features of these 23 studies were summarized in Table 1 for miR-200c and Table 2 for miR-141. [score:1]
The heterogeneity was partly decreased in Caucasians in some subgroup analyses (OS for miR-200c: I [2] = 70.7%; OS for miR-141: I [2] = 61.5%). [score:1]
These results indicated that the pooled HRs of overall analyses are too crude to present accurate prognostic values of miR-200c and miR-141. [score:1]
The role of miR-200c and miR-141 has been studied extensively in various cancers, but the conclusions are inconsistent. [score:1]
Furthermore, in the sensitivity analysis for miR-141 with OS as the endpoint (Figure 7(c)), the result which was not changed confirmed the stability of the studies. [score:1]
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[+] score: 75
Although the expression of CDYL and RCOR3 is less obviously affected by overexpression of miR-141 and miR-200c in PANC-1 cells as compared to CtBP2 and ZEB1 (data not shown), we observed a downregulation of CDYL and RCOR3 on the protein level, when miR-141 or miR-200c were transiently transfected in PANC-1 cells (Figure 4d), suggesting that CDYL and RCOR3 are also targets of the miR141-200c cluster. [score:9]
CtBP2 has one miR-141 target site and one miR-200c target site, while ZEB1 and CDYL have two miR-200c target sites. [score:7]
During EMT, the miR-141-200c cluster and the tumor invasion suppressor gene E-cadherin are downregulated by ZEB1/2 [35]. [score:6]
We showed that overexpression of miR-141 and miR-200c led to reduced expression of CtBP2 and ZEB1 in human pancreatic carcinoma (PANC-1) cells (Figure 4a). [score:5]
e, Downregulation of CDYL and RCOR3 on protein level when miR-141 or miR-200c was transiently transfected. [score:4]
Since the miR-141-200c cluster and E-cadherin are both downregulated during EMT, it is tempting to speculate that more β-catenin would be made available for participating in transactivating downstream genes, which may contribute to the progress of cancer [4]. [score:4]
Finally, we experimentally verified that the miR141-200c cluster simultaneously targets several protein components of the CtBP/ZEB complex, implying an efficient regulation of a protein complex by a cluster of miRNAs. [score:4]
We experimentally verified that the miR-141-200c cluster targets different components of the CtBP/ZEB complex, suggesting a potential orchestrated regulation in epithelial to mesenchymal transition. [score:4]
Interestingly, several essential components of the CtBP/ZEB complex, namely ZEB1/2, CtBP2, RCOR3 (REST corepressor 3) and CDYL (Chromodomain Y-like protein), are predicted targets of the miR-141-200c cluster. [score:3]
Nevertheless, we found that the targets of the miR-141-200c cluster are significantly interconnected (P-value < 0.02, Table 4). [score:3]
Intriguingly, the miR-141-200c cluster also targets β-catenin, which is a shared component of cell adhesion and Wnt signalling [38]. [score:3]
RCOR3 has one miR-141 target site. [score:3]
The seed region of miR-141 differs to that of miR-200c by one nucleotide at position 4 of the miRNA; therefore, miR-141 and miR-200c have, based on the "seed" rule, different computationally predicted targets. [score:3]
b, Confirmation of the regulation of CtBP2 and ZEB1 by miR-141 and miR-200c on protein levels by immunoblots. [score:2]
CtBP/ZEB complex regulated by the miR-141-200c cluster. [score:2]
To explore this in detail we examined the protein complexes predicted to be co-ordinately regulated by the miR-141-200c cluster. [score:2]
Figure 4Protein complexes regulated by the miR-141-200c cluster. [score:2]
The interaction between the miR-141-200c cluster and multiple components of the CtBP/ZEB complex suggests a coordinated regulation of the repression activity for the CtBP/ZEB complex. [score:2]
Together, these experiments demonstrate, for the first time, that CtBP2, CDYL and RCOR3 can be regulated by miR141-200c cluster post-transcriptionally. [score:2]
This supports our finding that the miR141-200c cluster also interacts with the CtBP complex. [score:1]
UB, SSB, YW and TB designed miR141-200c related experiments. [score:1]
The miR-141 and miR-200c genes are located on chromosome 12p 13.31, separated by a 338bp spacer sequence; miR-141 and miR-200c belong to the miR-200 family. [score:1]
PANC-1 stable clones for miR-141 or miR-200c were obtained with sequence verified pRetroSuper-miRNA plasmids. [score:1]
To demonstrate this, we experimentally verified that the miR141-200c cluster interacts with four different components of the CtBP/ZEB complex. [score:1]
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[+] score: 74
Other miRNAs from this paper: hsa-mir-205, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a, hsa-mir-587
These results suggest that the upregulation of N-BLR expression in colon cancer cells could regulate the acquisition of EMT phenotype by buffering the levels of both miR-141-3p and miR-200c-3p resulting in the upregulation of their target gene ZEB1. [score:12]
Data are shown as mean ± SEM: EMPTY n = 4, WT N-BLR n = 5, pyk90-DEL N-BLR n = 7. (Student’s t-test; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001) Having shown the inverse correlation between N-BLR and N-BLR and the ZEB1 -targeting miR-141-3p and miR-200c-3p, we sought to determine whether the modulation of N-BLR could influence the expression levels of ZEB1 and, by extension, the levels of E-cadherin. [score:5]
Thus, in this context, an increase in the expression levels of N-BLR, such as we observed in the cell lines and the CRC samples, can induce a concomitant interaction between N-BLR and available copies of the endogenous miR-141-3p/miR-200c-3p pool resulting in a reduced targeting of ZEB1. [score:5]
To prioritize among the miR-200 family’s members, we used the rna22 algorithm [45] to predict putative miRNA targets: miR-141-3p and miR-200c-3p were predicted to target N-BLR (Additional file 3: Figure S10A). [score:5]
N-BLR localizes to the cytoplasm where it directly interacts with miR-141-3p and miR-200c-3p, two members of the highly conserved miR-200 family known to inhibit EMT [44]. [score:4]
More interestingly, the ectopic expression of the pyk90-DEL N-BLR transcript, which lacks part of the miR-200c-3p binding site, could not induce the reduction of miR-200c-3p levels (Fig.   5b and c), whereas it was still able to significantly affect miR-141-3p levels (Additional file 3: Figure S14E and F). [score:3]
N-BLR overexpressing vectors were transiently co -transfected with either miR-141-3p or miR-200c-3p into HT-29 cells. [score:3]
b miR-200c-3p expression levels following 48 h of co-transfection with empty pcDNA 3.1 vector, pyk90-DEL N-BLR vector, pyk90-DEL N-BLR del miR-200c-3p, pyk90-DEL N-BLR double del for both miR-200c-3p and miR-141-3p binding sites. [score:3]
We particularly observed that an increase in the levels of N-BLR was associated with decreased levels of miR-141-3p and miR-200c-3p and accordingly increased levels of ZEB1, whereas a decrease of N-BLR levels was associated with opposite effects on miR-141-3p, miR-200c-3p, and ZEB1 expression. [score:3]
miR-141-3p and miR-200c-3p interaction with N-BLR influence ZEB1 expression. [score:3]
The pcDNA3.1-WT N-BLR and pcDNA3.1-pyk90-DEL N-BLR constructs carrying the single deletion for either miR-200c-3p or miR-141-3p binding sites, the double deletion for both miRs’ binding sites and the deletion between the miR-200c-3p and miR-141-3p binding sites synthesized by using Quik-Change II XL Site-Directed Mutagenesis kit (Stratagene, Agilent Technologies) and named WT N-BLR- del-miR200c, WT N-BLR- del-miR141, WT N-BLR double del, pyk90-DEL N-BLR- del-miR200c, pyk90-DEL N-BLR- del-miR141, pyk90-DEL N-BLR double del, and pyk90-DEL2 N-BLR. [score:2]
As expected, ectopic expression of WT N-BLR significantly reduced the levels of miR-200c-3p and miR-141-3p compared with the corresponding variants containing the deleted binding sites for each miRNA (Fig.   5a and Additional file 3: Figure S14C-E). [score:2]
Interestingly, when we transiently knocked down N-BLR in Colo320 cells, we noted a concomitant increase in the levels of miR-141-3p and miR-200c-3p (Fig.   4a). [score:2]
Next, we examined whether the 20-nt pyknon motif from the 844-nt long N-BLR transcript could affect the direct coupling of miR-141-3p and miR-200c-3p to N-BLR. [score:2]
This further confirmed indirectly the inverted correlation between the two short ncRNAs (miR-141-3p and miR-200c-3p) and the lncRNA N-BLR. [score:2]
Luciferase activity is decreased only when miR-141-3p and miR-200c-3p are co -transfected with the WT construct but not when a mutated vector is used. [score:1]
We confirmed a direct molecular coupling between both miR-141-3p and miR-200c-3p and N-BLR using luciferase assays and constructs carrying either the wild-type (WT) or the mutant miRNA response element sites within N-BLR (Fig.   4b). [score:1]
We found that low levels of both miR-141-3p and miR-200c-3p were associated with a poor OS of CRC patients (Additional file 3: Figure S12A and B right), and high levels of N-BLR associated with poor OS (Fig.   1c and d). [score:1]
Having established that the levels of N-BLR are inversely correlated to those of miR-141-3p and miR-200c-3p, we sought to determine whether this finding persists in clinical samples as well. [score:1]
On the contrary, in the transiently overexpressing N-BLR R KO cells that were used for the migration/invasion assays shown in Additional file 3: Figure S8, the levels of miR-141-3p and miR-200c-3p were significantly reduced compared with cells transfected with empty vector control (Additional file 3: Figure S10D). [score:1]
Y-axis values represent the ratio of miR-200c-3p and miR-141-3p to U6. [score:1]
We used individual vectors containing the following sequences: (1) WT N-BLR; (2) N-BLR with the miR-141-3p binding site deleted (WT N-BLR del miR-141-3p); (3) N-BLR with the miR-200c-3p biding site deleted (WT N-BLR del miR-200c-3p); and (4) N-BLR with both the miR-200c-3p and miR-141-3p binding sites deleted (WT N-BLR double del). [score:1]
We constructed pcDNA3.1 plasmids containing either WT N-BLR or pyk90- deleted N-BLR (pyk90-DEL construct from position 779 to 798 of N-BLR); then, for each of the two N-BLR variants we constructed a set of mutant vectors carrying the deletion either for miR-141-3p or miR-200c-3p binding sites or both (Additional file 3: Figure S14B). [score:1]
Similarly, when we transfected R KO cells with either miR-141-3p or miR-200c-3p mimics, the levels of N-BLR were decreased by ~30% (Additional file 3: Figure S11). [score:1]
These results made us conclude that these three non-coding transcripts (N-BLR, miR-141-3p, and miR-200c-3p) and three coding genes (E-cadherin, vimentin, and ZEB1) comprise a new component of signaling interactions in the EMT pathway. [score:1]
b A luciferase vector including the full N-BLR sequence (pGL3-N-BLR) as well as vectors that were mutated separately at the interaction sites of either miR-141-3p or miR-200c-3p [pGL3-N-BLR(M)] were constructed. [score:1]
The miR-200c-3p and miR-141-3p LNA probes were purchased from Exiqon. [score:1]
In summary, our findings suggest a mo del whereby N-BLR may mediate the switch from an epithelial to a mesenchymal cell phenotype by sequestering miR-141-3p and miR-200c-3p. [score:1]
a. miR-200c-3p levels following 48 h of co-transfection with empty pcDNA 3.1 vector, WT N-BLR vector, WT N-BLR del miR-200c-3p, WT N-BLR double del for both miR-200c-3p and miR-141-3p binding sites in HT-29 cell lines. [score:1]
The mirVana miRNA Mimics hsa-miR-200c-3p, hsa-miR-141-3p (MC11714, MC10860, Life Technologies), and mirVana miRNA Mimic Negative Control #1 were used for transfection at a final concentration of 50 nM. [score:1]
We also confirmed in R KO cells that transient transfection with the WT N-BLR vector could lower the levels of miR-141-3p and miR-200c-3p (Additional file 3: Figure S10D) and could increase the levels of ZEB1 (Additional file 3: Figure S15B). [score:1]
To quantify the levels of N-BLR, miR-141-3p, and miR-200c-3p in the ISH of tissue microarray, images of each tissue core were automatically captured using a Perkin Elmer Caliper Vectra 2 microscope and then analyzed using inForm 2.0 image analysis software (Perkin Elmer, Inc. [score:1]
Particularly in adenocarcinoma, high N-BLR levels were associated with low levels of miR-141-3p and miR-200c-3p. [score:1]
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[+] score: 73
Other miRNAs from this paper: hsa-mir-21, hsa-mir-1-2, hsa-mir-143, hsa-mir-1-1
In summary, we have demonstrated for the first time predominant stromal expression of miR-1 and miR-143 in prostate tissue, predominant epithelial expression of miR-141, and both stromal and epithelial expression of miR-21. [score:7]
Ectopic expression of miR-21 enhances PCa cell proliferation and tumor growth, and it imparts therapeutic resistance, while ectopic over -expression of miR-141 enhances PCa cell survival and suppresses stemness 16, 18– 21. [score:7]
These data indicate a predominantly stromal expression pattern for miR-1 and miR-143, and a predominantly epithelial expression pattern for miR-141. [score:5]
These results show a generally tissue-restricted expression pattern for miR-1 and miR-141, and a broader and higher level expression pattern for miR-143 and miR-21, across multiple tissue types. [score:5]
The expression of miR-21 (hsa-miR-21-5p) and miR-141 (hsa-miR-141-3p) are frequently reported to be elevated in human PCa, while the levels of miR-1 (hsa-miR-1-p3) and miR-143 (hsa-miR-143-3p) are frequently found to be decreased [8]. [score:3]
Compartmentalized expression of miR-1, miR-141, and miR-143 in normal human prostate. [score:3]
Figure 2Compartmentalized expression of miR-1, miR-141, and miR-143 in normal human prostate tissue. [score:3]
The predominant epithelial expression of miR-141 was also verified in these samples (10 fold, p = 0.026), with an average of 6.3 copies detected in epithelium and only 0.6 copies detected in stroma. [score:3]
Figure 3Cell and tissue type specific expression of miR-1, miR-143, miR-141, and miR-21. [score:3]
Extremely low levels of miR-141 could be detected in stromal tissue and cell cultures, indicating that miR-141 expression is predominantly, but not exclusively, epithelial. [score:3]
Levels of miR-141 had a moderate and inverse correlation with stromal MYH11, with a Pearson’s r value of −0.26 (p < 2.2 × 10 [−16]), suggesting epithelial rather than stromal gene expression (Fig.   6E). [score:3]
Expression of miR-1, miR-21, miR-141, and miR-143 in normal human cells and tissues. [score:3]
Four miRNAs have been frequently reported to have aberrant expression in PCa: miR-1, miR-21, miR-141, and miR-143. [score:3]
N1), and the dichotomized expression (using optimal thresholds) of miR-1, miR-141, and miR-21 were significantly associated with biochemical recurrence (Table  1A). [score:3]
miR-141 expression was lowest in muscle and heart tissues, and highest in epithelial-rich tissues such as skin, thyroid, and pancreas (Fig.   3B). [score:3]
In contrast to miR-1 and miR-143, miR-141 expression was predominantly epithelial in human tissues and cell cultures. [score:3]
The RT-ddPCR results show that these JHU samples have similar trends of elevated miR-21 and miR-141 in PCa, and reduced miR-1 and miR-143 (Fig.   1B). [score:1]
Conversely, miR-141 was almost exclusively detected in epithelium, with an average of 45 epithelial copies and only 5 stromal copies. [score:1]
Consistent with these results, we found miR-141 to be significantly elevated in PCa. [score:1]
miR-141 was detected at high levels in LNCaP, BPH1, and PrEC cells, while levels in fibroblast cells were extremely low (<0.001 copies). [score:1]
Significant differences could not be detected between normal and cancerous epithelium, or stroma, for miR-141 or miR-21 (Fig.   4C). [score:1]
The levels of miR-141 were also low (<10 [3] RPM) in most tissues. [score:1]
Consistent with our analyses in human tissue, we found increased levels of miR-21 (1.1 fold, p < 0.001) and miR-141 (1.3 fold, p < 0.001) in PCa cases, and decreased levels of miR-143 (2.6 fold, p < 0.001) (Fig.   6A). [score:1]
miR-21 and miR-141 levels are elevated in human PCa, and miR-1 and miR-143 levels are reduced. [score:1]
Conversely, miR-21 and miR-141 levels are frequently elevated in human PCa 14– 17. [score:1]
Unfortunately, we were not able to detect significant stromal- or epithelial-specific changes in miR-21 or miR-141 in microdissected PCa. [score:1]
Conversely, miR-141 and miR-21 levels were significantly higher in PCa by 1.5 fold (p = 0.01) and 1.9 fold (p = 0.025). [score:1]
miR-141 was initially reported as a potential diagnostic serum biomarker for PCa [15]. [score:1]
TaqMan MicroRNA RT (Applied Biosystems, Life Technologies) was used to generate cDNA for hsa-miR-21-5p, hsa-miR-143-3p, hsa-miR-141-5p, hsa-miR-1-5p, cel-miR-39, and RNU6B from 10 ng of RNA. [score:1]
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[+] score: 68
As we found that hsa_circRNA_100395 was significantly downregulated in PTC tumors here, our analysis suggests that miR-141-3p and/or miR-200a-3p should be consequently upregulated in PTC tumors as a result of regulatory disinhibition. [score:10]
This upregulation of miR-141-3p and/or miR-200a-3p may have effects on several cancer-related target genes that have been previously associated with these two miRNAs, including E2F3, GLS, CCND2, PTEN, CCNG1, CDC25B, and ZFPM2 (Tables 4 and 5). [score:6]
By comparing the lists of top-ranking cancer-related target genes, we were able to identify seven promising cancer-related genes that may be targets of the hsa_circRNA_100395/miR-141-3p/ miR-200a-3p axis in PTC (in order of descending rank): E2F3, GLS, CCND2, PTEN, CCNG1, CDC25B, and ZFPM2 (Tables 4 and 5). [score:5]
Further studies should focus on the dysregulation of the hsa_circRNA_100395/miR-141-3p/miR-200a-3p axis in PTC tumor cells in order to conclusively determine which cancer-related target genes are affected. [score:4]
However, miR-141-3p has been shown to be upregulated in nasopharyngeal carcinoma cells [34], lung carcinoma cells [35], ovarian tumor cells [36], prostate tumor cells [37], and bladder cancer cells [38]. [score:4]
From this analysis, we identified several promising cancer-related genes that may be targets of the dysregulated hsa_circRNA_100395/ miR-141-3p/miR-200a-3p axis in PTC tumors. [score:4]
Therefrom, we identified one promising downregulated circRNA in PTC tumors (hsa_circRNA_100395) that shows interactive potential with two cancer-related miRNAs (miR-141-3p and miR-200a-3p). [score:4]
With respect to the current study, both miR-141-3p and miR-200a-3p have been shown to regulate tumor growth and metastasis across several malignancies; however, the direction of miR-141-3p’s dysregulation is dependent upon the specific tissue type. [score:4]
From this analysis, we identified several promising cancer-related genes that may be targets of the dysregulated hsa_circRNA_100395/miR-141-3p/miR-200a-3p axis in PTC tumors. [score:4]
For example, miR-141-3p and miR-200a-3p have been shown to be downregulated in breast cancer cells [29, 30], gastric cancer cells [31], and renal cell carcinoma cells [32, 33]. [score:4]
One downregulated circRNA (hsa_circRNA_100395) showed interactive potential with two cancer-related miRNAs (miR-141-3p and miR-200a-3p). [score:4]
Top-ten ranking cancer-related target genes for hsa-miR-141-3p. [score:3]
0170287.g007 Fig 7(A) The targeted pathway heatmap analysis revealed significant correlations (depicted in red) between cancer-related pathways and two miRNA clusters: the miR-141-3p/miR-15a-5p/miR-23b-3p cluster and the miR-200a-3p/miR-214-3p cluster. [score:3]
In order to further investigate which miRNAs may be cancer-related, we applied several bioinformatics tools to identify one promising downregulated circRNA in PTC tumors (hsa_circRNA_100395) that shows interactive potential with two cancer-related miRNAs (miR-141-3p and miR-200a-3p) (Fig 7, S3, S4 and S5 Figs). [score:2]
From the initial list of 71 potential miRNAs identified from the aforementioned Arraystar analysis, the DIANA-miRPath platform was able to identify two cancer-related miRNA clusters within our pre-defined p-value<0.05 threshold: the miR-141-3p/miR-15a-5p/miR-23b-3p cluster and the miR-200a-3p/miR-214-3p cluster (Fig 7A, S3, S4 and S5 Figs). [score:1]
We then applied seed sequence matching on the IntaRNA platform to predict that hsa_circRNA_100395 has the potential to bind to both miR-141-3p and miR-200a-3p (Fig 7C). [score:1]
Comparing these two miRNA clusters to the Arraystar network map (Fig 6), we were able to identify that hsa_circRNA_100395 interacts with two miRNAs (miR-141-3p and miR-200a-3p) from the identified cancer-related miRNA clusters (Fig 7B). [score:1]
The hsa_circRNA_100395/miR-141-3p/ miR-200a-3p axis may be involved in the pathogenesis of PTC. [score:1]
Moreover, our bioinformatics analysis suggests that the hsa_circRNA_100395/miR-141-3p/ miR-200a-3p axis may be involved in the pathogenesis of PTC. [score:1]
Interestingly, both miR-141-3p and miR-200a-3p are members of the miR-200 family, which contains two miRNA clusters located on human chromosomes 1 and 12 (miRs-200a/b/429 and miRs-141/200c) [28]. [score:1]
Moreover, our bioinformatics analysis suggests that the hsa_circRNA_100395/miR-141-3p/miR-200a-3p axis may be involved in the pathogenesis of PTC. [score:1]
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[+] score: 64
At 40 weeks of age, the expression of miR-216, miR-217, miR-223, miR-141, miR-483-3p (p-value = 0.031), miR-195, Let-7b (p-value = 0.063) and miR-96 were significantly downregulated; on the other hand, the expression of miR-21, miR-205, miR-146b (p-value = 0.031), and miR-34c (p-value = 0.063) were upregulated in KC mice compared to the control animals (Figure 2C). [score:10]
The expression of miR-223, miR-483-3p (p-value = 0.01), 146b, 205 (p-value = 0.001), 221, 21 (p-value = 0.023), 195, 34c and miR-26a (p-value = 0.0078) were significantly upregulated, whereas the expression of miR-216, miR-141, miR-217, Let-7b (p-value = 0.001), and Let-150 (p-value = 0.01) were significantly downregulated in human PC tissues as compared to the cancer-adjacent normal tissues (Figure 3E). [score:10]
Further, Kent et al. (2009) reported downregulation of miRNA-200 family members, including miRNA-141, in PC cell lines [48] and observed a positive correlation between the expression of miR-200 family members and E-cadherin expression, as well as a negative correlation with the zinc-finger E-box -binding homeobox 1 (ZEB1) [48, 49]. [score:8]
At 10 weeks of age, expression of miR-141 and Let-7b were upregulated, but their expression was not statistically significant. [score:8]
The panel of differentially expressed miRNAs were validated by real-time PCR using TaqMan assays, and the results were consistent with the data that showed up-regulation of miR-21, miR-221, miR-100 and miR-26a and down-regulation of miR-26b, miR-141, miR-96, miR483-3p, miR-216, and miR-217 in the KC compared to control mice (Figure 1A). [score:7]
We have shown that in tumor samples compared to normal samples, the majority of miRNAs (miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, Let-7b, Let-195 and miR-96) were downregulated, and few were upregulated (miR-146b, miR-205, miR-31, miR-192, miR-194 21, miR-379, miR-431, miR-541, and miR-199b). [score:6]
Further, at 50 weeks of age, the expression of miR-216, miR-217, miR-345, miR-141, miR-483-3p, miR-26b, miR-96, Let-7b (p-value = 0.01), miR-100, miR-26a and miR-150 (p-value = 0.094) were further downregulated in KC animals compared to control mice (Figure 2D). [score:5]
In addition to pancreas-specific miRNAs, we observed significant downregulation of miR-141 and Let-7b in human PDAC and in KC mice from 25–50 weeks of age compared to controls (Figure 1A, 2B– 2D, 3E). [score:3]
The transcription of miR-200 family members (miR-141 and miR-200c) is suppressed by ZEB1, which activates epithelial differentiation in PC, colorectal, and breast cancer cells. [score:3]
Therefore, existence of a feedback loop between ZEB1 and miR-141 serves to stabilize the EMT process and regulate the invasion of cancer cells [49]. [score:2]
Our human PDAC results were in agreement with earlier reports showing loss of Let-7b and miR-141 expression in PC samples compared to cancer-adjacent normal tissue [46, 47]. [score:2]
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[+] score: 60
From our data, we found that both miR-200c and miR-141 were over-expressed in over half of the NPC patient group, which was clinically diagnosed as metastasis stage 0. Monitoring the change of their expression levels may serve as an indicator for the disease progression as it has been proven that high level of both miR-141 and 200c will lead to increased expression of E-cadherin, eventually causing inhibition on tumour progression and metastasis. [score:11]
Over -expression of miR-141 and miR-200c caused down-regulation of ZFHX1B and up-regulation of E-cadherin in two renal carcinoma cell lines [20]. [score:9]
It was confirmed that miR-141 and miR-205 were dramatically down-regulated in Splunc 1 expressed cell. [score:6]
Zhang et al. reported that miR-141, found to be up-regulated in NPC specimens in comparison with normal nasopharyngeal epithelium, is involved in NPC-related genes network by targeting BRD3, PTEN and UBAP1. [score:6]
On the other hand, inhibition of miR-141 significantly decreases the viability of Splunc 1-expressed cells with cell cycle arrest in the G0–G1 phase and decreases in cell migration and invasion ability. [score:5]
Vrba L Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cellsPLoS One. [score:4]
A recent publication demonstrated that ZFHX1B (also known as SIP1 and ZEB2), a transcriptional repressor for CDH1/E-cadherin, is a target of both miR-141 and -200c. [score:3]
Inhibition of miR-141 could affect cell cycle, apoptosis, cell growth, migration and invasion in NPC cells [22]. [score:3]
By considering the fold-change threshold and percentage of incidence, among the 95 screened miRNAs which have functional significance with regard to potential roles in cancer, cell development and apoptosis, ten miRNAs (miR-205, miR-196a, miR-149, miR-183, miR-224, miR-210, miR-150, miR-136, miR-200c and miR-141) were identified which may play a putative role in cancer development, metastasis and have potential as biomarkers for the detection of NPC. [score:3]
The incidence of up and down regulation of these ten miRNAs, including miR-205 (94.1%), miR-196a (88.2%), miR-149 (82.4%), miR-183 (64.7%), miR-224 (58.8%), miR-210 (58.8%), miR-136 (47.1%), miR-200c (64.7%), miR-141 (52.9%) and miR-150 (82.4%) between non-NPC controls and NPC patients ranges from about 47% to 94% incidence rate. [score:2]
Tamagawa S Role of miR-200c/miR-141 in the regulation of epithelial-mesenchymal transition and migration in head and neck squamous cell carcinomaInt. [score:2]
Tejero R miR-141 and miR-200c as markers of overall survival in early stage non-small cell lung cancer adenocarcinomaPLoS One. [score:1]
The miR-141 and miR-200c, which belong to the miR-200 family, have been shown to play a critical role in the EMT in various malignancies including breast, renal clear cell, gastric, and bladder [19]. [score:1]
Zhang L microRNA-141 is involved in a nasopharyngeal carcinoma-related genes networkCarcinogenesis. [score:1]
They were miR-205, miR-196a, miR-149, miR-183, miR-224, miR-210, miR-136, miR-200c, miR-141 and miR-150. [score:1]
Among them, miR-141, 149, 200c, and 205 have been reported in the NPC mo dels. [score:1]
These suggested that miR-141 might play an important role as an oncogene in NPC tumourigenesis [22]. [score:1]
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22
[+] score: 56
SEMA6A was confirmed as a direct target of miR-141 by over -expressing miR-141 in a ccRCC cell line and showing strong down-regulation of the SEMA6A transcript. [score:9]
In epithelial cells, miR-200 family microRNAs and E-cadherin maintain higher level expression by repressing ZEB1, ZEB2 and TGFβ; on the other hand, in mesenchymal cells and tumors, the up-regulation of ZEB factors is triggered by TGFβ and suppresses the transcription of miR-141/200c by binding to their putative common promoter region. [score:8]
Our hypothesis (prediction) from these various observations is that in normal kidney, the expression level of HIF2α and its downstream targets (VEGFA, TGFβ etc) are regulated by miR-141, 200a*, 200b and 200c and the loss of this microRNA regulation, in concert with VHL loss, is responsible for activation of the HIF pathway. [score:7]
Finally, to establish that this method can accurately predict functional and direct microRNA/mRNA regulation, we performed an in vitro analysis of one microRNA (miR-141), and its identified direct target SEMA6A. [score:6]
The results (Figure 5) showed that introduction of pre-miR-141 produced a significant reduction in the level of SEMA6A mRNA, validating SEMA6A as a functional and direct target of miR-141. [score:4]
As confirmation of these results, down-regulation of miR-141 and miR-200c and their function on ZEB2 in ccRCC has recently been reported [87]. [score:4]
In vitro validation of SEMA6A as a target of miR-141. [score:3]
For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX), VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1, ERBB4, and (SLC12A1, TCF21) respectively. [score:3]
Figure 5 Validation of a Direct interaction between miR-141 and SEMA6A. [score:2]
As the p-values in Figure 4 indicate, we validate a strong anti-correlation signature between mRNA levels of (KCNMA1, LOX), VEGF, SEMA6A, (LRRC2, PTPN13), SFRP1, ERBB4, SLC12A1 and TCF21, and their identified regulators: miR-149, miR-200c, mir-141, miR-142-3p, miR-185, mir-34a, miR-224 and miR-21 respectively. [score:2]
One intriguing association which we have identified (miR-141 regulation of SEMA6A) is highly significant for therapy in ccRCC. [score:2]
We also found strong anti-correlation between VEGFA and the miR-200 family of microRNA: miR-200a*, 200b, 200c and miR-141. [score:1]
of in-vitro experiment on RCC cell line CRL-1611 transfected either with pre-miR-141 or a control pre-miR using either Fugene (Fu) or Hyfect (Hy). [score:1]
Hence, our results imply that miR-141 may have a role in gene therapy. [score:1]
The regulation of SEMA6A by miR-141 was verified by a transfection assay. [score:1]
Human renal cell adenocarcinoma cells (ATCC, CRL-1611) were transfected with either the negative control pre-miR or hsa-miR-141 (Ambion) using either FuGENE HD (Roche) or HyFect (Denville scientific) transfection reagents. [score:1]
There is clear reduction in mRNA of SEMA6A upon introduction of miR-141 by either transfection method in these cells. [score:1]
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23
[+] score: 54
Other miRNAs from this paper: hsa-mir-205, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a, hsa-mir-429
In our breast cancer samples, we found that low expression of the mir-141/mir-200c cluster was associated with activated signaling via the PI3K–AKT pathway, which concurs with recent data suggesting that p53 negatively regulates the ZEB–E-cadherin pathway by upregulating mir-200s [23]. [score:7]
In the epithelial cells of normal mucosa and primary and metastatic colorectal samples ISH revealed mir-141 to be specifically expressed, but no detectable differences in the level of expression between the stages of progression were found in these matched samples, although there was a trend towards higher expression in the metastatic leasion (Figure 1e and f). [score:7]
Furthermore, there was a positive correlation between mutated PIK3CA status and ZEB1 (R = 0.30, p = 0.0042), whereas there was a negative correlation between PIK3CA mutations and expression of mir-141/mir-200c (R = –0.23, p = 0.032). [score:4]
In support of that assumption, we found a negative correlation between mutated p53 and high expression of mir-141 (R = –0.26, p = 0.012) and mir-200c (R = –0.21, p = 0.039), which agrees with recently reported data suggesting that p53 is a negative regulator of the EMT pathway [23]. [score:4]
The localization of microRNA expression was determined by microRNA in situ hybridization (ISH) using a locked nucleic acid (LNA) probe for mir-141 and control probes for mir-205, nuclear U6, and scrambled microRNA, together with a MicroRNA ISH kit for FFPE tissues (Exiqon). [score:3]
0084815.g004 Figure 4In the group of breast cancer patients that did not receive chemotherapy, low expression of mir-141/200c was associated with significantly worse outcome in terms of distant recurrence-free survival (HR = 2.74, [CI 95% 1.08–6.99, p = 0.034]) (a). [score:3]
In the group of breast cancer patients that did not receive chemotherapy, low expression of mir-141/200c was associated with significantly worse outcome in terms of distant recurrence-free survival (HR = 2.74, [CI 95% 1.08–6.99], p = 0.034) (Figure 4a). [score:3]
Low expression of the mir-141/200c cluster was associated with a decrease in distant recurrence-free survival, which implies that these EMT markers can be useful prognostic factors in cancer. [score:3]
For the survival analyses, a combination variable, mir-200, was created and defined as high expression (upper quartile) of mir-141 and/or mir-200c. [score:3]
In the group of breast cancer patients that did not receive chemotherapy, low expression of mir-141/200c was associated with significantly worse outcome in terms of distant recurrence-free survival (HR = 2.74, [CI 95% 1.08–6.99, p = 0.034]) (a). [score:3]
According to the Sanger microRNA database, brain tissue shows very little or no expression of mir-141, and thus we used such tissue as a negative control (NC) and confirmed that no ISH signal was present (e). [score:3]
Compared to normal epithelial cells, primary colorectal cancer cells, but not metastatic cells, showed a significant decrease in mir-141 expression. [score:2]
Our results demonstrate that the indicated EMT markers can be useful treatment predictive factors in cancer, as mir-141/200c can serve as a predictor of response to radiation or chemotherapy in tumor progression. [score:1]
In matched human colorectal cancer samples, the levels of mir-141 were significantly lower in metastatic tissue than in normal tissue (p=0.043) (a). [score:1]
0084815.g001 Figure 1In matched human colorectal cancer samples, the levels of mir-141 were significantly lower in metastatic tissue than in normal tissue (p=0.043) (a). [score:1]
Interestingly, mir-141 was positively correlated with ER status (R = 0.31, p = 0.0019), whereas mir-200c was negatively correlated with HER2 status (R = –0.25, p = 0.013), suggesting that these microRNAs play disparate roles in different subtypes of breast cancer. [score:1]
Mir-141 showed strongest expression in epithelial cells of the liver metastases as compared to normal tumor-adjacent mucosa and primary colorectal tumor (e, f). [score:1]
There are five members of the mir-200 family, which are clustered together at two polycistronic sites: mir-200a, mir-200b, and mir-429 are located on chromosome 1p36 [13]; and mir-200c and mir-141 are located on chromosome 12p13. [score:1]
Since mir-141/200c had proven to be of greatest clinical relevance in the analyses of metastatic colorectal cancer samples, this microRNA cluster was further focused on in the analyses of the breast cancer material. [score:1]
We also observed that mir-141 was correlated with positive ER status, whereas mir-200c was negatively associated with HER2 status, which suggests that these microRNAs play different roles in different subtypes of breast cancer. [score:1]
Considering clinicopathological variables, mir-200c was negatively correlated with lymph node status (R = –0.24, p = 0.0047), and mir-141 was negatively correlated with S-phase fraction (R = –0.22, p = 0.035). [score:1]
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24
[+] score: 48
They also demonstrated that miR-141 directly targets KEAP1, and downregulation of KEAP1 by miR-141 overexpression induced cisplatin resistance. [score:9]
Of 29 miRs, they showed that only 4 (miR-141, miR-200a, miR-200b, and miR-200c) were upregulated and 25 were downregulated, including miR-199a, miR-140, miR-145, and miR-125b-1 in the cancer samples [21]. [score:7]
In ovarian cancer, 11 miRs were upregulated (miR-16, miR-20a, miR-21, miR-23a, miR-23b, miR-27a, miR-93, miR-141, miR-200a, miR-200b, and miR-200c) and 12 were downregulated (miR-10b, miR-26a, miR-29a, miR-99a, miR-100, miR-125a, miR-125b, miR-143, miR-145, miR-199a, miR-214, and let-7b). [score:7]
Van Jaarsveld et al. compared the miR expression profiles of cisplatin-sensitive and -resistant ovarian cancer cells, revealing that high expression of miR-141, miR-200c, miR-215, and miR-421 and low expression of miR-492-5p correlated with increased cisplatin resistance [61]. [score:6]
Members of the miR-200 family (miR-141, miR-200a, miR-200b, miR-200c, and miR-429) are downregulated in the majority of ovarian cancers, as previously described [21, 23]. [score:4]
The researchers compared the expression profiles of 8 miRs (miR-21, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, and miR-214) between cancer tissues and exosomes collected from the peripheral sera of the corresponding patients, since these had been previously demonstrated to be overexpressed in ovarian cancer. [score:4]
Eight key miRs (miR-25, miR-29c, miR-101, miR-128, miR-141, miR-182, miR-200a, and miR-506) were identified and predicted to regulate 89% of the targets in this network. [score:4]
From integrated genomic analysis, 8 key miRs (miR-25, miR-29c, miR-101, miR-128, miR-141, miR-182, miR-200a, and miR-506) were predicted to regulate 89% of the miR targets in the network [26]. [score:4]
Both miR-141 and miR-200a target p38 and modulate the oxidative stress response, affecting tumorigenesis and chemosensitivity [55]. [score:3]
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25
[+] score: 46
For example, Ho et al. (2011) reported that an enterovirus could stimulate miR-141 expression and inhibit the host protein translation by targeting eIF4E to increase viral propagation. [score:9]
Under this condition, miR-141 and miR-200c were not up-regulated, and miR-21-3p and miR-29b-1-5p were only slightly down-regulated at 8 hpi (Figure 3D). [score:7]
Enterovirus -induced miR-141 contributes to shutoff of host protein translation by targeting the translation initiation factor eIF4E. [score:7]
Together, these results supported the conclusion that miR-141 and miR-200c were up-regulated, while miR-21-3p and miR-29b-1-5p were down-regulated during IAV infection of human cells. [score:7]
Another recent report showed that miR-141 and miR-200c potentially targeted Sdc2, which is involved in HSV-1 cellular attachment and entry (Majer et al., 2017). [score:3]
Effect of avian influenza A H5N1 infection on the expression of microRNA-141 in human respiratory epithelial cells. [score:3]
Chemically synthesized miRNA mimics and miRNA inhibitors (miR-141-3p, miR-200c-3p, miR-21-3p, and miR-29b-1-5p) were purchased from RiboBio (China). [score:3]
These results showed that inactive IAV was not essential for the regulation of miRNAs, including miR-141, miR-200c, miR-21-3p, and miR-29b-1-5p. [score:2]
Here, we used miRNA profiling to investigate the differentially expressed miRNAs during H1N1 and H5N1 infection in A549 cells and found that a subset of four miRNAs, including miR-141, miR-200c, miR-21-3p, and miR-29b-1-5p, was dysregulated at both 8 hpi and 24 hpi. [score:2]
A subset of five miRNAs was both dysregulated at 8 h and 24 h post-infection, including miR-141, miR-200c, miR-21 [*] (also known as miR-21-3p), miR-29b-1 [*] (also known as miR-29b-1-5p) and miR-663. [score:2]
miR-141 and miR-200c were both increased at 8 and 24 hpi in H5N1-infected cells, while they were only increased at 24 hpi in H1N1-infected cells (Figures 2C,D). [score:1]
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26
[+] score: 45
The multiple miRNAs dysregulated in the breast CSCs, such as miR-142, miR-146, miR-200, and miR-141, cooperatively activate the Wnt signaling pathway by targeting or upregulating the expression of its components. [score:9]
ZEB1 suppresses the expression of all miR-200 family members (miR-141, miR-200a,b,c and miR-429), which in turn inhibits the translation of ZEB1 mRNA, resulting in the double -negative ZEB/miR-200 feedback loop [160]. [score:9]
Among them, miR-200b, miR-200c, miR-141, and miR-183 are specifically downregulated in the human breast CSCs and normal mammary stem/progenitor cells [24], suggesting that miRNAs are important regulators of self-renewal abilities in breast CSCs and normal mammary stem/progenitor cells (Figure 3). [score:5]
miR-200a and miR-141 suppress the Wnt signaling pathway by targeting β-catenin [150, 151]. [score:5]
miR-200b, miR-200c and miR-141 target Bmi1 which suppresses p53 -mediated cell cycle arrest and apoptosis by repressing p19 [Arf](Figure 2 and Figure 3). [score:5]
The expression of Bmi1 is regulated by miRNAs, such as miR-128, miR-200b/c, miR-141, miR-15, miR-16, miR-203, miR-183, miR-194, and miR-218 [24, 67, 121, 122, 123, 124, 125]. [score:4]
The miR-200 family is highly expressed within epithelial cells and miR-200c and miR-141 have both been strongly linked to epithelial integrity [158, 159]. [score:3]
Abedi N. Mohammadi-Yeganeh S. Koochaki A. Karami F. Paryan M. miR-141 as potential suppressor of β-catenin in breast cancer Tumour Biol. [score:3]
Among them, miR-200a, miR-200b and miR-429 are found in all deuterostomes including Echinodermata, Chordata and Vertebrata, but miR-200c and miR-141 are only detected in cephalochordates, teleosts and mammals or in tunicates, teleosts and mammals, respectively. [score:1]
The miR-200 family in mammals is composed of five miRNAs: miR-200a, miR-200b, miR-200c, miR-141, and miR-429. [score:1]
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27
[+] score: 42
In both yellow catfish and human, down-regulation of miR-141 and 429 was observed during the progression of testis development [17]. [score:5]
miR-141 and miR-200a inhibit protein expression of p38α. [score:5]
Although tumorigenesis is promoted by overexpression of miR-200a or miR-141, overexpression of miR-200a and miR-141 also increases tumor-cell death and slows tumor growth under treatment with paclitaxel, a chemotherapeutic drug known to increase ROS. [score:5]
Peng T. Zhang S. Li W. Fu S. Luan Y. Zuo L. MicroRNA-141 inhibits glioma cells growth and metastasis by targeting TGF-β2Am. [score:4]
3′-UTR of TGF-β2 contains a target site for miR-141/200a [63, 64]. [score:3]
Resistance to paclitaxel and carboplatin was induced when inhibitors of miR-200c or miR-141 were transfected into the parental OVCAR-3. Notably, both OVCAR-3/TP and MES-OV/TP cells regained sensitivity to carboplatin but only MES-OV/TP regained sensitivity to taxol [117]. [score:3]
Introduction of miR-200c and miR-141 mimics into OVCAR-4/TP resulted in alternation in expression of genes related to oxidative stress. [score:3]
YY testis (super-males), which has a higher degree of testis maturity, had relatively lower expression of miR-141 and miR-429 when compared with XY testis. [score:2]
Besides Taxol, miR-200c and miR-141 also regulate sensitivity to carboplatin. [score:2]
Mateescu B. Batista L. Cardon M. Gruosso T. de Feraudy Y. Mariani O. Nicolas A. Meyniel J. P. Cottu P. Sastre-Garau X. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress responseNat. [score:1]
In a study with two ovarian cancer cell lines, OVCAR-3 and MES-OV, and their paclitaxel resistant variants OVCAR-3/TP and MES-OV/TP, resistant variants OVCAR-3/TP showed a marked decrease in miR-200c and miR-141. [score:1]
These five miRNAs form two clusters: cluster 1 of miR-200b, miR-200a and miR-429 maps to chromosome 1 (1p33.36), while the miR-200c and miR-141 cluster maps to chromosome 12 (12p13.31) [4]. [score:1]
miR-200c and miR-141, but not miR-200b, were reported to be associated with chemosensitivity in ovarian cancer. [score:1]
Gao Y. C. Wu J. MicroRNA-200c and microRNA-141 as potential diagnostic and prognostic biomarkers for ovarian cancerTumour. [score:1]
Accumulation of miR-141 and miR-200a mimicked p38α deficiency and promoted malignancy in mouse mo dels. [score:1]
Only high miR-200c levels and low miR-141 levels were significantly associated with a good survival rate [126]. [score:1]
In a study of serum miR-200 levels in 74 ovarian cancer patients, both miR-200c and miR-141 were significantly elevated in cancer sera than in healthy control [126]. [score:1]
This miRNA family consists of five members: miR-200a, miR-200b, miR-200c, miR-141 and miR429. [score:1]
miR-200b, miR-200c and miR-429 (Functional Group I) all share the same seed sequence (5′-AAUACUG-3′), while miR-200a and miR-141 (Functional Group II) both share the same seed sequence (5′-AACACUG-3′), with the two functional groups differing in the seed sequence only by one nucleotide [5]. [score:1]
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28
[+] score: 39
Dysregulation of MIR101, MIR141, and MIR152 to the HIV-1 Gag protein contributes to HIV-1 budding and release via DNA hypermethylation, ubiquitin transfer, and endoplasmic reticulum -associated degradation at the late infection stage Briefly, dysregulation of; dysregulation of MIR9 contributes to HIV-1 infection to hijack CD4+ T cells through dysfunction of the immune and hormone pathways; dysregulation of MIR139-5p, MIRLET7i, and MIR10a contributes to the HIV-1 integration/replication stage through DNA hypermethylation and immune system dysfunction; dysregulation of MIR101, MIR141, and MIR152 contributes to the HIV-1 virus assembly/budding stage through DNA hypermethylation, ubiquitin transfer, and endoplasmic reticulum -associated degradation; dysregulation of MIR302a contributes to not only microvesicle -mediated transfer of miRNAs but also dysfunction of NF-κB signaling pathway in hepatocarcinogenesis. [score:7]
We found that dysregulation of; dysregulation of MIR9 contributes to HIV-1 infection to hijack CD4+ T cells through dysfunction of the immune and hormone pathways; dysregulation of MIR139-5p, MIRLET7i, and MIR10a contributes to the HIV-1 integration/replication stage; dysregulation of MIR101, MIR141, and MIR152 contributes to the HIV-1 virus assembly and budding mechanisms; dysregulation of MIR302a contributes to not only microvesicle -mediated transfer of miRNAs but also dysfunction of NF-κB signaling pathway in hepatocarcinogenesis. [score:6]
In this study, we identified that the 3 genetic and epigenetic regulations, including the gain of the miRNA regulation of MIR141 to JMJD1C (p-value < 0.789) and the genetic regulation of TP73 to GADD45A (p-value < 0.037) in cancer cells, and DNA methylations of JMJD1C and GADD45A, led to not only changes of gene expression profiles of JMJD1C (p-value < 7.3☓10 [-11]) and GADD45A (p-value < 7.3x☓10 [-11]) but also changes of DNA methylation profiles of JMJD1C (p-value < 0.014) and GADD45A (p-value < 0.096) between human normal liver cells and liver cancer cells (Fig.   4). [score:6]
Therefore, the expression changes of MIR101, MIR141, and MIR152 (p-value < 0.037, p-value < 0.108, and p-value < 0.126, respectively) contributed to the expression change of Gag (p-value < 0.090). [score:5]
Recently, it has been found that the overexpressed MIR141 results in extensive DNA damage [80], and JMJD1C and TP73 are the components of DNA-damage response pathway with implications for tumorigenesis [81, 82]. [score:3]
Dysregulation of MIR101, MIR141, and MIR152 to HIV-1 budding and releasing through DNA hypermethylation, ubiquitin transfer, and endoplasmic reticulum -associated degradation at the virus assembly/budding infection stage. [score:2]
At the late infection stage, we determined that regulation of MIR101, MIR141, and MIR152 to Gag (p-value < 1☓10 [-16]) results in dysfunction of the infected cells through a signaling cascade of 5 proteins, PRMT1, inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), autocrine motility factor receptor (AMFR), tripartite motif containing 25 (TRIM25), and ubiquitin-conjugating enzyme E2N (UBE2N) (Fig.   7). [score:2]
Dysregulations of DNA methylation and MIR141 contribute to dysfunction of DNA damage response in HCC. [score:2]
Therefore, we suggested that the dysregulations of DNA methylation and MIR141 give rise to dysfunction of DNA damage response in HCC. [score:2]
Dysregulations of MIR141 and MIR335 contributes to dysfunction of DNA damage response and cell proliferation in human HCC, respectively Moreover, we also identified that 5 genes have basal level difference between Hepatocellular Carcinomas (HCCs) and normal cells, including ELAVL1 (P-value < 3.69☓10 [-5]), JMJD1C (P-value < 3.59☓10 [-11]), GADD45A (P-value < 7.32☓10 [-11]), EIF2AK3 (P-value < 5☓10 [-5]), and GSN (P-value < 1.19☓10 [-2]), which is mainly due to DNA methylation of the corresponding genes (Fig.   4). [score:2]
Therefore, we suggested that the UBE2N -associated ubiquitin transfer is induced by a signaling cascade leading to dysregulation of MIR101, MIR141, and MIR152. [score:2]
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[+] score: 37
We observed a significant overexpression of miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429, miR-520b (all p<0.001) in UUTUC; the microRNAs miR-10a (p = 0.012) and miR-200b (p = 0.006) showed a distinct trend towards upregulation, whereas miR-1244 (p = 0.600) was similar in normal and malignant tissue. [score:6]
The expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) formerly shown to be upregulated in urothelial bladder cancer were studied in corresponding normal and cancerous tissue samples of patients undergoing nephroureterectomy for UUTUC. [score:6]
MicroRNA expression allowed differentiation of normal and cancerous tissue: miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were significantly overexpressed. [score:5]
In order to investigate the role of microRNAs as non-invasive biomarkers in patients with UUTUC, the expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) earlier shown to be upregulated in urothelial cancer of the bladder [13– 20], was analyzed [11] in corresponding normal ureter and UUTUC tissue. [score:4]
Especially miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were distinctly overexpressed in UUTUC. [score:3]
The microRNA expression levels in serum are displayed in Fig. 2. miR-141 was circulating at significantly higher levels (p<0.001) in serum of UUTUC patients than in control subjects (mean 1.30 vs. [score:3]
An overexpression of miR-141 is involved in KEAP1-regulated cisplatin resistance [31], and thus miR-141 measurements could be helpful for the monitoring of patients undergoing cisplatin chemotherapy for metastatic UUTUC. [score:2]
The TarBase 6.0 [32], a database with experimentally validated microRNA-gene interactions, indicates that miR-141 regulates various genes (for example PTEN [33], ERBB2IP [34], HOXB5 [34], E2F3 [33], cyclin D1 [33]) involved in urothelial carcinogenesis (database query: 06–03–2014). [score:2]
The finding of increased urinary miR-141 levels in bladder cancer patients supports the idea of miR-141 as a diagnostic tool [28]. [score:1]
Stage and grade could explain this difference: high serum miR-141 levels were observed in many studies in advanced stages [24, 25] or patients with recurrence after surgery [25– 27]; however, miR-141 was not correlated with any prognostic parameter in our study on UUTUC. [score:1]
It should be noted that circulating miR-141 levels are elevated in multiple tumor entities including prostate cancer [25], colon cancer [29] and cervical cancer [30]. [score:1]
ROC analyses demonstrated that miR-141 allowed distinguishing UUTUC patients and controls with an AUC of 0.726 (sensitivity 71% and specificity 74%) indicating that circulating miR-141 is a suitable diagnostic biomarker. [score:1]
The analysis of circulating miR-141 may be useful to identify patients with UUTUC. [score:1]
ROC analysis demonstrated an AUC of 0.726 (95% confidence interval 0.609–0.843) for miR-141 as diagnostic biomarker; see Fig. 3 and Table 2. miR-200b (p = 0.041), miR-205 (p = 0.008), miR-425 (p = 0.025), miR-96 (0.013) showed a trend towards higher levels in cancer patients, but the p-value was >0.0065 which was defined as significance level after correction for multiple hypothesis testing. [score:1]
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30
[+] score: 33
Down -expression of DDX5 was observed in 7 types of HCs, while, mir-20b, mir-21, mir-141 and mir-182 over-expressed in 3, 5, 3 and 4 HCs, respectively (Table 3 and Table 4). [score:5]
For example, mir-141 and, mir-200c, which were over-expressed in 3 HCs (shown as purple in the Figure 3), have miRNA effects on ZEB2 (with down -expression in 7 HCs). [score:5]
Amplification of 12p13 region was observed in breast cancer [37], T cell lymphomas and lymphocytic leukemia [38], [39], causing over -expression of GAPDH, mir-141 and -200c. [score:3]
DDX5 is negatively regulated by mir-20b and mir-141, while DDX5 itself regulates mir-21 and mir-182. [score:3]
Our results showed that up regulation of mir-20b and mir-141 down regulates DDX5. [score:3]
Thirteen downstream targets were observed for mir-141, mir-200c, and GAPDH. [score:3]
Network of common altered variants in different cancers including mir-200c, mir-141, and GAPDH at 12p13.3. [score:1]
This subnetwork comprises 5 entities including DDX5, mir-20b, mir-21, mir-141 and mir-182. [score:1]
0096320.g002 Figure 2Network is including mir-21, mir-182, -mir20b and mir-141. [score:1]
Among common altered miRNAs, mir-21, mir-30a, mir-141 and mir-200c were shared across all of the four constructed networks (Table S5). [score:1]
Second subnetwork (Figure 3) contained GAPDH, mir-141 and mir-200c that are located at 12p13.31 as predicted PCSRs. [score:1]
Network analysis indicates that DDX5, LIFR, ZEB2, mir-21, mir-27b, mir-30a, mir-141, mir-182 and mir-200c were shared across different constructed networks, indicting their crucial role in cancer biology and progression, which has been reported previously [28], [29], [30]. [score:1]
Another subnetwork was constructed based on mir-141, mir-200c, and GAPDH, which all located on predicted PCSRs at 12p13.31 (Figure 3). [score:1]
In these subnetworks, different RNAs are located on PCSRs including GAPDH, ZEB2, mir-20b, mir-21, mir-141 and mir-200c supporting the important effects of these RNAs and their regions in cancer. [score:1]
The subnetwork centered on DDX5 with total 5 nodes and 4 relations (Figure 2) and the subnetwork of GAPDH, miR-141 and mir-200c confirm such interactions (Figure 3). [score:1]
Network is including mir-21, mir-182, -mir20b and mir-141. [score:1]
Interestingly, these altered RNAs including mir-141, mir-200c and GAPDH (at 12p13.31) and also ZEB2 (at 2q22.3) are all located at predicted PCSRs. [score:1]
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Conclusively, this systematic review and validation experiment demonstrated four up-regulated miRNAs (miR-200a, miR-200b, miR-200c and miR-141) and one down-regulated miRNA (miR-100) are promising important candidate biomarkers for EOC. [score:7]
Particularly, all of them (miR-200a, miR-200b, miR-200c, and miR-141), four up-regulated miRNAs of the five most consistently expressed miRNA among the eight profiling studies, belong to the miR-200 family. [score:6]
To validate the expression of the five most consistently reported miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c), that may be the candidate biomarkers for EOC, the expression of these miRNAs between EOC and normal ovarian tissues were compared using qRT-PCR analysis. [score:4]
Accordingly, miR-200b and miR-141 could be a novel target for enhancing chemosensitivity or inducing cell death in ovarian cancer. [score:3]
Moreover, inhibition of miR-141 using anti-miR-141 decreased cell growth in choloangiocarcinoma cell lines [23]. [score:3]
Figure 1 qRT-PCR analysis of miR-200a, miR-100, miR-141, miR-200b, and miR-200c expressions in the EOC and normal ovarian tissues. [score:3]
Excitingly, among the 17 miRNAs, 5 promising differentially miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c) were reported with the consistent direction in four or more studies. [score:2]
More importantly, 5 differentially miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c) were reported with the consistent direction among four or more studies (Table  5). [score:2]
MiR-200a and miR-200b are located on chromosome 1, while miR-200c and miR-141 are on chromosome 12. [score:1]
MiR-200a and miR-100 were reported in 6 studies; MiR-141 and miR-99a were reported in 5 studies; MiR-200b and miR-200c were reported in 4 studies and 11 miRNAs (miR-143, miR-145, miR-214, miR-134, miR-154, miR-424, miR-29a, miR-21, miR-10b, miR-26a, and let-7d) were reported in 3 studies. [score:1]
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Hu et al., 2016 [74] Pancreatic cancer PANC-1 and SW1990 cells Down RT–PCR Fenofibrate inhibits pancreatic cancer cells proliferation mediated by upregulation of MEG3Li et al., 2016 [56] Glioma U251, U87 and A172 Down qRT-PCR DNMT1 -mediated MEG3 hypermethylation causes the loss of MEG3 expression, followed by the inhibition of thesZhang et al., 2016 [63] CC HeLa and CaSki Down qRT-PCR MEG3 may interact with miR-21-5p to affects the post-transcriptional networkZhou et al., 2015 [57] GC MKN45 and 7901 Down qRT-PCR miR-141 could interact with MEG3 and target E2F3Peng et al., 2015 [59] GC HGC-27,MGC-803, MKN-45, SGC-7901, BGC-823 and AGS Down qRT-PCR MEG3 could up-regulated Bcl-2 via its competing endogenous RNA activity on miR-181aLuo et al., 2015 [60] PC PC3 and DU145 Down qRT-PCR MEG3 inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phaseYin et al., 2015 [54] CRC HCT-116 and DLD-1 cell lines Down qRT-PCR MEG3 inhibits cell proliferation through TP53 activation. [score:22]
Furthermore, E2F3 was identified as a target of miR-141, and its expression level was also found to be negatively associated with both MEG3 and miR-141 [57]. [score:5]
These findings may indicate the interaction between miR-141 and MEG3 to inhibit GC cell proliferation. [score:3]
In another study, the levels of miR-141 and MEG3 have been found to be significantly reduced in GC patients. [score:1]
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The top 15 differentially expressed microRNAs based on fold change (p<0.05) are presented in Table 1. The most differentially expressed miRNA was mmu-miR-429, a member of the miR-200 family, and 4 of the 5 miR-200f members (miR-141, miR-200b, miR-200c and miR-429) were in the top 15 differentially expressed miRNAs (shaded in Table 1). [score:7]
It should however be noted that one recent manuscript reported that re-expressed the miR-141/200c cluster in the human claudin-low breast cancer cell line, MDA-MB-231, found that miR-141/200c re -expression was associated with increased migration [80]. [score:5]
Quantitative RT-PCR was used to validate the differential expression of the miR-200 family and as shown in Table 2, all 5 members of the miR-200f (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) were expressed at significantly higher levels in the PMT samples compared to the RST samples. [score:4]
First, targeted bisulfite sequencing of a putative miR-200c/miR-141 promoter region was performed in RJ345, RJ423 and RJ348 cell lines as well as in PMT and RST samples. [score:3]
Previous reports indicate that the miR-200c/miR-141 promoter region can be methylated and this methylation decreases miR-200c and miR-141 expression [44– 47]. [score:3]
This family of microRNAs is expressed as two clusters on distinct chromosomes with the miR-200c/miR-141 cluster located on chromosome 12 in humans and chromosome 6 in mice and the miR-200b/miR-200a/miR-429 cluster located on chromosome 1 in humans and chromosome 4 in mice [15]. [score:3]
Expression (mean ± SEM) of miR-200a, miR-200b, miR-200c, miR-141 and miR-429 in RJ345 cells, RJ423 cells containing the empty vector control (RJ423EV) or RJ423 cells containing miR-200c (RJ423200c) as determined by Taqman RT-PCR. [score:3]
Evaluation of the methylation status of 30 CpG sites ~1000bp upstream of the miR-200c/miR-141 cluster on murine chromosome 6 as determined by targeted bisulfite sequencing. [score:1]
miR-200a and miR-141 share the same seed sequence (AACACUG) that is different from the seed sequence of miR-200b, miR-200c and miR-429 by one nucleotide [16]. [score:1]
One family of microRNAs that has garnered considerable attention in cancer biology is the miRNA-200 family (miR-200f) which consists of 5 members, miR-141, miR-200a, miR-200b, miR-200c and miR-429. [score:1]
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In order to further understand the role of aberrant miRNAs in physiological functions and biologic processes in arsenite -induced neoplastic transformation cells, 11 downregulated miRNAs (miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, and miR-33b-5p) and six upregulated miRNAs (miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, and miR-141-3p) (Table S2) were selected, and their target genes were predicted with the TargetMiner, miRDB, and TarBase databases. [score:11]
Among the 191 dysregulated miRNAs, seventeen miRNAs (downregulation miRNAs: miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, miR-33b-5p; upregulation miRNAs: miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, miR-141-3p, Table S2) were selected for bioinformatics analysis. [score:8]
Three of downregulated miRNAs (miR-192b-5p, miR-15b-5p, and miR-33b-5p) and three upregulated miRNAs (miR-141-3p, miR-106b-5p, and miR-200b-3p) (Table S2) were selected for validating the reliability of analysis results from miRNA Array. [score:7]
Also, miR-141-3p, miR-106b-5p, and miR-200b-3p expression levels of HBE-T cells were 2.29-, 10.51-, and 14.47-fold of that in HBE cells. [score:3]
We determined the level of six miRNAs (miR-33b-5p, miR-15b-5p, miR-192-5p, miR-141-3p, miR-200b-3p, and miR-106b-5p) to validate the reliability of the miRNA Array detection. [score:1]
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Most interestingly, 3 of these resistance-relevant miRNA candidates showed a similar pattern of deregulation in both tumour types: miR-141 and miR-200b were significanty upregulated whereas miR-376a was significantly downregulated (see Table  1 and Figure  6). [score:8]
Specifically, PPI treatment led to upregulation of miR-141 and miR-200b and downregulaton of miR-376a in SCC and EAC cells. [score:7]
Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types. [score:7]
Imanaka et al. reported that miR-141 was highly expressed in cisplatin-resistant SCC cell lines [39], and van Jaarsveld and colleagues found an association between miR-141 levels and response to cisplatin therapy in ovarian cancer patients [40]. [score:3]
Most interestingly, we found three miRNAs (namely miR-141, miR-200b and miR-376a) to be deregulated in a similar fashion in both tumour subtypes, implying that these miRNAs might in general be affected by PPI treatment. [score:2]
Namely, we selected miR-16, miR-21, miR-23a, miR-24, miR-26a, miR-106, miR-141, miR-155, miR-196a, miR-200a, miR-200b, miR-200c, miR-221, miR-222, miR-296-5p, miR-376a, miR-429 and let-7i for this study. [score:1]
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TRAF6 and TAOK3 are inhibited by mir-373, GYK and APPBP2 are inhibited by mir-200a, TRAF6, TAOK3 and ZNF302 are inhibited by mir-141, CBX2 is inhibited by mir-1, APBB1 is inhibited by mir-148b, POLR3D is inhibited by mir-374b, NAE1 is inhibited by mir-503, and GTF2I is inhibited by mir-98. [score:17]
The specific core GEN of old women demonstrated that TAOK3 and TRAF6 are inhibited by mir-141 and mir-373, respectively, and DNA methylation of MAX, TAOK3, and MYD88 in order to overcome dysregulation of the MAPK signaling and Toll-like receptor signaling pathways as well as dysfunctions of the immune system, proliferation, and metabolism. [score:4]
In addition, TAOK3 and TRAF6 are inhibited by mir-141 (c [il] = −0.2235-TAOK3; c [il] = −0.36144-TRAF6) and mir-373 (c [il] = −0.10454-TAOK3; c [il] = −0.12645-TRAF6). [score:3]
However, TRAF6 is also inhibited by mir-141, and is also involved in the Toll-like receptor signaling pathway. [score:3]
Pathway analyses demonstrated that there are two core miRNAs, mir-373 and mir-141 (Figure 13). [score:1]
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In particular, the robust association of miR-141, miR-200b, and miR-375 with metastatic disease is noteworthy: These markers could potentially be applied at the time of diagnosis to identify patients with aggressive disease/micrometastases, and/or to predict recurrence following primary treatment. [score:5]
miR-141 is a member of the miR-200 family, which functions to repress the epithelial to mesenchymal transition (EMT) by targeting the ZEB family of transcription factors [123]. [score:3]
It was recently shown to act on ovarian tumorigenesis by targeting p38α and modulating the oxidative stress response [124], while circulating plasma miR-141 was also identified as a novel marker for metastatic colon cancer predicting poor prognosis [125]. [score:3]
They found a remarkably higher expression of miR-141, as detected by qRT-PCR, in prostate cancer than in control samples. [score:3]
As there is an urgent need to increase the diagnostic specificity of prostate cancer tests, while maintaining—or even increasing—sensitivity, combination of a miRNA signature, including e. g., circulating miR-141, miR-125b, miR-200b, and miR-375 [118, 126, 130], with traditional protein markers, could translate into a better diagnostic tool with higher specificity, sensitivity, and accuracy, suitable for population-wide screening efforts. [score:3]
Various miRNAs were highly abundant in the sera of patients with metastatic disease, including miR-141, miR-375, miR-9-3p, miR-200b and miR-516a-3p. [score:3]
We recently achieved amplification-free detection of prostate cancer-specific (miR-141 and miR-375) and lung cancer-specific (miR-30d-5p and miR-25-3p) miRNAs at subpicomolar concentrations (T. K. and A. R., unpublished). [score:1]
Further validation identified circulating miR-141 and miR-375 to be the most pronounced markers for high-risk tumors. [score:1]
Taking advantage of the observed stability of tumor-derived miRNAs in circulating blood, Mitchell et al. evaluated the expression of miR-141 in a case-control cohort of serum samples. [score:1]
A recent study identified 16 miRNAs, including miR-141, miR-200b, and miR-375, at differential levels in the plasma of men with localized or metastatic prostate cancer [130]. [score:1]
Cheng et al. [125] found that circulating miR-141 was significantly associated with Stage IV colon cancer in a cohort of 102 plasma samples and that combination of miR-141 and carcinoembryonic antigen (CEA), a wi dely used marker for CRC, further improved the accuracy of detection. [score:1]
Thus, plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis, and high levels of miR-141 in plasma are associated with poor prognosis [125]. [score:1]
Additionally, their analysis demonstrated that high levels of plasma miR-141 predicted poor survival and that miR-141 was an independent prognostic factor for advanced colon cancer. [score:1]
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To investigate the cellular mechanism for the hypothesis that high miRNA expression is associated with tumor cell progression, we transfected the three miR inhibitors (miR-141*, miR-205, miR-182) into the endometrial cancer cells (Hec1A) to down-regulate miRNA activity. [score:6]
The up-regulated miRNA was miR-200a* miR-205, miR-141*, miR-200b*, miR-141, miR-200b, miR-200a, miR182. [score:4]
The up-regulation of the miR-200 family (miR-141, 200a, 200b) is observed consistently, despite the use of different patient populations and different tissue types (fresh vs. [score:4]
Among these miRNAs, five were up-regulated in tumor samples where the fold change was more than 5-fold (miR-200a*, miR-205, miR-141*, miR-200b*, miR182). [score:4]
Five miRNA genes (miR-200a*, miR-205, miR-141*, miR-200b*, miR182) were selected because of their notably high differential expression in tumor tissues in the microarray data. [score:3]
The miR-200 family and miR-141 are known to have similar seed sequences, meaning that it is highly probable that they share target genes. [score:3]
Therefore, we selected only miR-141 (instead of miR-200a* or 200b*) for the validation study with FFPE-derived tissues. [score:1]
We transfected with the five anti-miRNAs (anti-miR-141*, anti-miR-205, anti-miR-182, anti-miR-200a*, anti-miR-200b*) into the Hec1A cells and treated them with IC50 of cisplatin or paclitaxel for 48 hours. [score:1]
This miR-200 family is composed of five miRNAs localized on two genomic clusters: miR-200c and miR-141 on chromosome 12 and miR-200a, miR-200b and miR-429 on chromosome 1. Members of this family are known to be involved in the epithelial to mesenchymal transition (EMT) that occurs during tumor invasion and metastasis in uterine and other tissues [19]. [score:1]
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-96, mmu-let-7g, mmu-let-7i, mmu-mir-124-3, mmu-mir-9-2, mmu-mir-141, mmu-mir-152, mmu-mir-182, mmu-mir-183, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, mmu-mir-205, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-182, hsa-mir-183, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-205, hsa-mir-214, hsa-mir-200b, mmu-let-7d, mmu-mir-130b, hsa-let-7g, hsa-let-7i, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-96, hsa-mir-200c, mmu-mir-200c, mmu-mir-214, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-7a-1, mmu-mir-7a-2, mmu-mir-7b, hsa-mir-200a, hsa-mir-130b, hsa-mir-376a-1, mmu-mir-376a, dre-mir-7b, dre-mir-7a-1, dre-mir-7a-2, dre-mir-182, dre-mir-183, dre-mir-199-1, dre-mir-199-2, dre-mir-199-3, dre-mir-205, dre-mir-214, hsa-mir-429, mmu-mir-429, hsa-mir-450a-1, mmu-mir-450a-1, dre-mir-429a, dre-let-7a-1, dre-let-7a-2, dre-let-7a-3, dre-let-7a-4, dre-let-7a-5, dre-let-7a-6, dre-let-7b, dre-let-7c-1, dre-let-7c-2, dre-let-7d-1, dre-let-7d-2, dre-let-7e, dre-let-7f, dre-let-7g-1, dre-let-7g-2, dre-let-7h, dre-let-7i, dre-mir-7a-3, dre-mir-9-1, dre-mir-9-2, dre-mir-9-4, dre-mir-9-3, dre-mir-9-5, dre-mir-9-6, dre-mir-9-7, dre-mir-96, dre-mir-124-1, dre-mir-124-2, dre-mir-124-3, dre-mir-124-4, dre-mir-124-5, dre-mir-124-6, dre-mir-130b, dre-mir-141, dre-mir-152, dre-mir-200a, dre-mir-200b, dre-mir-200c, hsa-mir-450a-2, dre-let-7j, hsa-mir-376a-2, mmu-mir-450a-2, dre-mir-429b, mmu-let-7j, mmu-let-7k, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
We found eight miRs differentially expressed, six down-regulated (miR-9, miR-141, miR-200a, miR-200b, miR-429 and miR-376a) and two up-regulated (miR-450a-5p and miR130b*) in the Dlx5 [−/−] OE (Fig.  1a). [score:9]
We observed a reduction of miR-9, miR-141 and miR-429 signal in the Dlx5 [−/−] OE, compared to the WT (Fig.  1c), while hybridization with two positive controls, Sp8 (expressed in the OE) and Sox5 (expressed in chondrogenic condensations), yielded an equivalent positive signal in both genotypes, indicating adequate RNA preservation. [score:4]
For miR-141/ 200a, the enriched categories included regulation of cell differentiation, neurogenesis, development and regulation of transcription (Suppl. [score:4]
miR-200a, miR-200b, miR-141 and miR-429 share the same seed sequence and likely target the same mRNAs; for this reason they are grouped in a single miR class (named miR-200-class). [score:3]
As a further confirmation, we carried out in situ hybridization on sections of WT and Dlx5 [−/−] embryonic OE, at the age E12.5, to detect miR-9, miR-141 and miR-429, using specific mouse DIG -labelled probes. [score:1]
The miR-200a, - 200b and - 429 loci are closely located on chromosome 4, while miR-141 and -200c are closely located on chromosome 6. miR-376a is clustered with 16 other miRs on chromosome 12. [score:1]
Since miR-200a, miR-200b, miR-141 and miR-429 share very similar seed sequences (Suppl. [score:1]
No Dlx5 binding site was predicted within a 50 kb range from the miR-9.1, miR-141, miR-200c and miR-376a loci. [score:1]
Hybridization was carried out with DIG -labelled riboprobes that specifically detect the mature form of mouse miR-9 and miR-141 (Exiqon) in according with manufactory instruction. [score:1]
We carried out the same prediction and categorization analyses for the miR of the -200 class; in this case the two subfamilies (miR-141/ 200a and miR-200b/ c/ 429/ 548a) were examined separately, and indeed yielded lists which were similar but not identical. [score:1]
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Other miRNAs from this paper: hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-182
In addition, protein levels of ACLY (miR-27a target – Figure 7C), ZEB1 (miR-141 target – Figure 7D), PTEN (miR-141 target – Figure 7E) and FOXO1 (miR-182 and −27a target, Figure 7F) were significantly increased following addition of 99021, indicating derepression by their targeting miRs due to loss of GSK3β-enhanced miR biogenesis. [score:11]
To provide further evidence for the importance of GSK3β activity for miR maturation, converse experiments were performed using a vector expressing constitutively active GSK3β: GSK3β-S [9]A. Transfection of GSK3-S [9]A into HEK293T significantly increased levels of mature miR-27a, miR-23a, miR-24, miR-141 and miR-182 by up to 7.5-fold (Figure 2A), with similar effects also observed in HeLa cells (Supplementary Figure S2A). [score:3]
Constitutively active GSK3β S [9]A mutant increases Drosha cleavage activity and enhances MiR biogenesisTo provide further evidence for the importance of GSK3β activity for miR maturation, converse experiments were performed using a vector expressing constitutively active GSK3β: GSK3β-S [9]A. Transfection of GSK3-S [9]A into HEK293T significantly increased levels of mature miR-27a, miR-23a, miR-24, miR-141 and miR-182 by up to 7.5-fold (Figure 2A), with similar effects also observed in HeLa cells (Supplementary Figure S2A). [score:3]
We next examined whether 99021 treatment affected levels of the 3΄UTR of ACLY, ZEB1, PTEN and FOXO1 (miR-27a, miR-141, miR-141 and miR-182/27a targets, respectively). [score:3]
Similar effects were observed for pull down of pri-miR-141/200c and pri-miR-182 (Supplementary Figure S5). [score:1]
No significant difference in pri-miRs levels was observed between Flag-Drosha WT and S [300]E,S [302]D -transfected cells (Figure 6F), and whilst levels of miR-27a and −182 were not significantly altered in the presence of phospho -mimic Drosha (Figure 6Gii,iv), miR-23a and miR-141 levels were significantly increased in the presence of the S [300]E,S [302]D construct (Figure 6Gi,iii). [score:1]
It was demonstrated that transfection of Flag-Drosha significantly increased pri-miR-23a27a24-2 and pri-miR-182 pull-down by up to 4-fold over background binding (Figure 3Ai and iii), with a similar trend observed for pri-miR-141/200c (Figure 3Aii). [score:1]
Figure 2. GSK3β activation enhances MiR biogenesis and GSK3β modulation alters pre-miR synthesis (A) qRT-PCR analysis of miR-27a, miR-23a, miR-24, miR-141 and miR-182 levels in HEK293T cells transfected with pMT23-HA-GSK3β(S [9]A) for 48 h. U18 was used as a normalisation gene. [score:1]
It was found that pull-down of pri-miR-23a27a24-2 and pri-miR-141/200c was significantly increased in the presence of HA-GSKβ compared to empty vector control (Figure 3C), suggesting either that GSK3β is able to directly interact with pri-miRs, or that the presence of GSK3β in the MP (or MP-like complex) increases association of pri-miRs with this complex. [score:1]
Conversely, addition of constitutively active GSK3β-S [9]A significantly enhanced association of pri-miR-141/200c with Drosha by 5-fold (Figure 3Bii) and the same trend was observed for both pri-miR-23a27a24-2 and pri-miR-182 (Figure 3Bi and iii). [score:1]
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In pre-miR-141 transfected cells, ABL2 (c-Abl oncogene 2, a non-receptor tyrosine protein kinase) and proto-cadherin 10 (PCDH10) expression was reduced, while Snail expression was induced, suggesting GEN targets EMT regulating mechanisms in renal cancer [109]. [score:8]
Indeed, miR-141 was shown to bind to and suppress HOTAIR expression. [score:5]
Similar to reports in prostate cancer, the lncRNA HOTAIR is significantly higher expressed in renal carcinoma cells compared to normal kidney, whereas miR-141 is significantly lower expressed, suggesting a link between the two RNAs. [score:4]
Chiyomaru T. Fukuhara S. Saini S. Majid S. Deng G. Shahryari V. Chang I. Tanaka Y. Enokida H. Nakagawa M. Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells J. Biol. [score:4]
Treatment with GEN induced miR-141, and consequently repressed HOTAIR expression. [score:3]
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A significant number of genes associated with metastasis were overexpressed in tumors classified into the serum miRNA cluster 1. (A) Box plots representing microarray expression results for miR-141, miR-200b, miR-193b and miR-301 from two different studies performed in lung primary tumors. [score:5]
Two of the miRNAs included in the supervised miRNA signature are also up-regulated in the serum of patients diagnosed with other types of cancers, such as prostate (miR-141) and pancreatic cancer (miR-200b) 8 19. [score:4]
A supervised diagnostic miRNA signature composed of 4 miRNAs (miR-141, miR-200b, miR-193b and miR-301) which were up-regulated in NSCLC tumors and serum was selected to validate its diagnostic value in an independent cohort of age and sex-matched serum samples. [score:4]
Validation results showed that all 4 miRNAs were significantly overexpressed in the NSCLC sera (p < 0.001) and the log [2] fold-change for miR-141, miR-200b, miR-193b and miR-301 were 2.67, 2.98, 2.52 and 2.01 respectively. [score:3]
We identified 4 miRNAs that fulfilled these criteria: miR-141, miR-200b, miR-193b and miR-301, since they were significantly overexpressed in lung AC and/or SCC versus normal lung samples (Fig. 3A) as well as in the serum of NSCLC patients versus NC (Fig. 3B). [score:3]
Only 5 miRNAs were found overexpressed in both lung AC and lung SCC primary tumors (miR-141, miR-200b, miR-193b, miR-200c and miR-106b) as well as in the NSCLC serum. [score:3]
Although the inclusion of miR-141 and miR-200b may reduce the specificity of the proposed miRNA signature, this signature discriminated between NSCLC patients and matched controls with outstanding accuracy in the validation set. [score:1]
To validate these findings, we measured by RT-PCR the expression level of miR-141, miR-200b, miR-193b and miR-301 in the serum of an independent cohort of 84 NSCLC and 23 age and sex-matched NC subjects. [score:1]
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[+] score: 23
miR-451 targeting CPNE3 and RAB5A, [25] and miR-141 targeting CXCL12B [26] have known functions on leukocyte chemotaxis and migration [26]. [score:5]
miR-141 could potentially activate angiogenesis (FLT1, THBS1) and ECM remo deling (TIMP1, SERPINE1) by reducing the inhibitory effect on target mRNAs. [score:5]
In NEC tissues, we showed that down-regulation of miR-141 could activate ECM remo deling (TIMP1, SERPINE1) and angiogenesis (FLT1, THBS1). [score:4]
Huang et al. proposed that miR-141 targeting CXCL12B might contribute to the development of intestinal inflammation by recruiting inflammatory cells in mice having colitis [26]. [score:4]
Although many IBD -associated miRNAs did not appear to be dysregulated in preterm NEC tissues, several miRNAs, including miR-223, miR-132, miR-146b-3p, miR-215, miR-375, miR-31 and miR-141, were regulated in both IBD and NEC. [score:3]
Levels of 15 miRNAs: miR-223, miR-1290, miR-4725-3p, miR-4793-3p, miR-410, miR-187, miR-375, miR-203, miR-200b-5p, miR-194-3p, miR-200a, miR-215, miR-31, miR-192-3p and miR-141 were significantly different between NEC and SIP tissues (0.12–59.05 fold; Table 2). [score:1]
A recent study has shown that treatment with miR-141 was effective in reducing intestinal inflammation in the mouse mo del of colitis [26]. [score:1]
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[+] score: 23
B, shown is a time series qRT-PCR data of miR-141 and miR-200b expression in zeb1b -overexpressing embryos (left side; injected with 100 pg zeb1b mRNA and 30 pg gfp mRNA) or zeb1a/b double morphants (right side; injected with 4 ng zeb1a/b TBMO) relative to control embryos (left side; injected with 130 pg gfp mRNA; right side; injected with 4 ng SCMO). [score:5]
Expression of miR-141 and -200b was significantly decreased in zeb1b -overexpressing embryos compared with control siblings during gastrulation and early segmentation. [score:4]
We measured the expression of miR-141 and miR-200b, located in the two different miR-200 family clusters, in zeb1b -overexpressing embryos and zeb1a/b morphants by qRT-PCR. [score:3]
To investigate their functional relevance, we generated miR-200 morphants by injection of a triple anti-miR-200 MO mix (miR-141 MO, miR-200b MO, and miR-429 MO) that was shown to efficiently knockdown all five members of the miR-200 family (23) and controlled our knockdown experiment for the absence of expression of these by whole-mount ISH of 2-day-old embryos (data not shown). [score:3]
miR-141 and miR-200b expression in control embryos was set to 1 (n = 4 per condition; values represent the mean ± S. E. ). [score:3]
To verify the efficacy of anti-miR-200 family MOs, one-cell stage embryos were injected with an anti-miR-200 MO mix (miR-141, -200b, -429) or SCMO, fixed at 48 h post fertilization (hpf), and assayed for miR-141, 200a/b/c, and -429 expression by whole-mount ISH. [score:2]
miR-200c and miR-141 map closely on chromosome 6, and the stem-loop sequences are separated by a 118-base pair spacer sequence. [score:1]
MOs against the miR-200 family are as published (23): anti-miR-141 (5′-GCA TCG TTA CCA GAC AGT GTT A-3′), anti-miR-200b (5′-GTC ATC ATT ACC AGG CAG TAT TA-3′), and anti-miR-429 (5′-ACGGCATTACCAGACAGTATTA-3′). [score:1]
Finally, we show that Zeb1b represses transcription of miR-141 and -200b, two members of the miR-200 family. [score:1]
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[+] score: 22
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-107, hsa-mir-16-2, hsa-mir-198, hsa-mir-148a, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181c, hsa-mir-182, hsa-mir-183, hsa-mir-205, hsa-mir-210, hsa-mir-181a-1, hsa-mir-222, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-27b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-132, hsa-mir-137, hsa-mir-140, hsa-mir-142, hsa-mir-143, hsa-mir-144, hsa-mir-153-1, hsa-mir-153-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-134, hsa-mir-136, hsa-mir-146a, hsa-mir-150, hsa-mir-184, hsa-mir-185, hsa-mir-186, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-128-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-299, hsa-mir-26a-2, hsa-mir-373, hsa-mir-376a-1, hsa-mir-342, hsa-mir-133b, hsa-mir-424, hsa-mir-429, hsa-mir-433, hsa-mir-451a, hsa-mir-146b, hsa-mir-494, hsa-mir-193b, hsa-mir-455, hsa-mir-376a-2, hsa-mir-33b, hsa-mir-644a, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-301b, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-320e, hsa-mir-3613, hsa-mir-4668, hsa-mir-4674, hsa-mir-6722
They found that the most significantly upregulated and downregulated miRNAs in scrapie-infected mice were, mmu-miRNA-3473e (9.48 log [2]) and mmu-miRNA-141-5p (-7.33 log [2]) in the 139A group, mmu-miRNA-3473e (13.18 log [2]) and mmu-miRNA-200a-5p (-7.08 log [2]) in the ME7 group, and mmu miRNA-3473e (14.15 log [2]) and mmu-miRNA-183-3p (-10.15 log [2]) in the S15 group (Gao et al., 2017). [score:7]
During clinical phase of prion disease all the members of the miRNA-200 family (miRNA-200a-3p, miRNA-200b-3p, and miRNA-200c-3p), miRNA-141-3p, and miRNA-429-3p and the 182 cluster (miRNA-182-5p and miRNA-183-5p) are downregulated (Boese et al., 2016). [score:6]
During clinical stage of prion disease, all members of the miRNA-200 family (such as miRNA-200a-3p, miRNA-200b-3p, miRNA-200c-3p), miRNA-141-3p, miRNA-429-3p, and 182 cluster miRNAs (miRNA-182-5p and miRNA-183-5p) were downregulated (Boese et al., 2016). [score:6]
Recently, Chang et al. (2016) showed that CRISPER-Cas9 targeted miRNA-17, miRNA-200c and miRNA-141, repressed their activity in human colon cancer cell lines HCT116 and HT-29. [score:3]
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[+] score: 22
Leukemia inhibitory factor (LIF), which is known to be a major regulator of trophoblast functions, has been reported to upregulate miR-21 and miR-93, but down-regulate miR-141, expression in JEG-3 cells [109]. [score:12]
Both miR-21 and miR-141 are highly expressed in placenta tissue and they are abundantly detected in maternal circulation [82, 153]. [score:3]
Silencing of miR-141 completely inhibited the proliferation of JEG-3 cells, suggesting that miR-141 promotes trophoblast cell proliferation [109]. [score:3]
MicroRNA-141 was highly expressed in first trimester trophoblast cells [92]. [score:2]
In addition, some miRNAs (miR-141, -149, -299-5p, and -135b) showed higher concentrations in the maternal plasma before delivery than after delivery [153]. [score:1]
Furthermore, some miRNA (i. e., miR-141) levels in plasma increase with the progression of gestation [153]. [score:1]
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[+] score: 22
In the present study both exogenous administration of RA and CYP26B1 inhibitor significantly up-regulated the expressions of cfa-miR-200a, cfa-miR-200b, cfa-miR-200c and cfa-miR-141 and reveals the involvement of these miRNAs with RA -dependent spermatogenesis. [score:8]
In an analysis of miRNA expression during primordial male germ cell development from embryonic day, E9.5 to E13.5 in mice, miR-200a, miR-200b and miR-141 expressions steadily decrease and reach the lowest level at the E13.5 [17]. [score:6]
MiRNA families such as miR-200 (cfa-miR-200a, cfa-miR-200b and cfa-miR-200c), Mirlet-7 (cfa-let-7a, cfa-let-7b, cfa-let-7c, cfa-let-7g and cfa-let-7f), miR-125 (cfa-miR-125a and cfa-miR-125b), miR-146 (cfa-miR-146a and cfa-miR-146b), miR-34 (cfa-miR-34a, cfa-miR-34b and cfa-miR-34c), miR-23 (cfa-miR-23a and cfa-miR-23b), cfa-miR-184, cfa-miR-214 and cfa-miR-141 were significantly up-regulated with testicular RA intervention via administration of CYP26B1 inhibitor and all-trans-RA (Figure 5). [score:6]
Cfa-miR-200a, cfa-miR-200b, cfa-miR-200c and cfa-miR-141 are clustered together in the same family. [score:1]
Cfa-miR-200a and cfa-miR-200b are transcribed from chromosome 5 and cfa-miR-200c and cfa-miR-141 are transcribed from chromosome 27. [score:1]
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[+] score: 21
For example, miR-200a and miR-200c were upregulated in all subtypes (mucinous, endometrioid, and clear cells), miR-200b and miR-141 were upregulated in serous as well as endometrioid carcinomas, and miR-21, miR-203, and miR-205 were upregulated only in endometrioid carcinomas. [score:10]
miR-200a and miR-141 were identified as highly upregulated in cancer, whereas miR-199a, miR-140, miR-145, and miR-125b1 were most significantly downregulated. [score:7]
The analyses highlights the important role of a miRNA regulatory network consisting of eight key miRNAs for the mesenchymal subtype including miR-141 and miR-200, miR-29c, miR-101, miR-506, and miR-128. [score:2]
miR-200a, miR-200b, and miR-429 are located on chromosome 1, while miR-200c and miR-141 are on chromosome 12. [score:1]
The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429 which are arranged in two clusters in the human genome. [score:1]
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[+] score: 21
Other miRNAs from this paper: hsa-mir-16-1, hsa-mir-16-2, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a
Firstly, in vitro methylation experiments showing how DNA methylation of the miR200c/141 locus shuts down expression of miR-200c and miR-141 provides a functional link between DNA methylation of the promoter and expression of the miR-200c/141 locus. [score:5]
With respect to the EMT process, observations suggest that members of the miRNA-200 family (especially the two clustered miRNAs miR-200c and miR-141) play a prominent role as metastasis suppressor genes by preventing the expression of zinc finger E-box binding homeobox 1 (ZEB1), which in turn promotes EMT and the switch to an invasive phenotype [4, 7- 10]. [score:5]
Whereas in vitro methylation of the miR-200c/141 promoter led to shutdown of promoter activity, treatment with a demethylating agent caused transcriptional reactivation in breast cancer cells formerly lacking expression of miR-200c and miR-141. [score:3]
Given the reported role of miRNA-200c and miRNA-141 in metastasis formation [16, 17] and, more recently, in tumorigenesis, development and stem cells homeostasis [14, 24] we speculated that this locus might be subject to epigenetic regulation. [score:3]
This might explain the observation previously made by us and others [4, 23] that miR-200c is usually expressed at higher levels compared to miR-141. [score:2]
Upon in-silico inspection, a high-score splice donor site (boundary exon/intron) was detected between the two miRNAs in position +373, supporting the existence of an alternative splicing variant that splices out miR-141 and conserves the miR-200c transcript. [score:1]
Recently, specific microRNAs (miRNAs), namely members of the miRNA-200 family including miR-200c and miR-141, have been implicated in this process [2- 4]. [score:1]
Bands shown for the miRNAs correspond to the mature forms of miR-141 (22bp) and miR-200c (23bp). [score:1]
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[+] score: 20
For some of these miRNAs the deregulated expression was not confirmed in all samples; miR-21 was deregulated in 50 % of FFPE samples, miR-335 in 54 %, miR-141 in 59 % and miR-221 in 67 %. [score:5]
The deregulated expression of the other miRNAs was confirmed (miR-9 in 100 %, miR-141 in 59 %, miR-200a in 87 %, miR-125b-2* in 89 %, miR-335 in 54 %, miR-221 in 67 %, miR-20b in 93 % of HPV -positive tumors and in 87 % of HPV -negative tumors, and miR-210 in 100 % of tumors of both etiologies). [score:4]
From the group of HPV core miRNAs, we selected miR-9, miR-141, and miR-200a which were upregulated in both groups of HPV -associated tumors (Additional file 9: Figure S3). [score:4]
In comparison with the expression profiles in cervical tumors, we defined miR-141-3p, miR-15b-5p, miR-200a-3p, miR-302c-3p, and miR-9-5p as specific for HPV induced malignancies. [score:3]
MiR-141 has been found to be overexpressed in HPV -positive cervical carcinomas [64]. [score:2]
Selected miRNAs (miR-21, miR-205, let-7b, miR-24, miR-126, miR-378, miR-141, miR-200c, miR-146b, miR-191, and miR-484) which were found differentially expressed by the microarrays in tonsillar samples were further validated by the individual RT qPCR using the TaqMan® MicroRNA Assays (Life Technologies, USA) on the same set of samples. [score:2]
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[+] score: 19
Specifically, five miRNAs (miR-26b, miR-26a, miR-212, miR-107, and miR-103) were upregulated and twelve miRNAs (miR-125b, miR-141, miR-144, miR-164, miR-145, miR-143, miR-15b, miR-16, miR-186, let-7b, let-7a3, and miR-128) were downregulated. [score:7]
In Amaral et al. 's study, although no association between miRNAs expression and tumor size was observed, the patients with ACTH-secreting pituitary tumors expressing reduced miR-141 had more chance of remission after transsphenoidal surgery, suggesting that miR-141 may regulate pituitary genes involved in tumor growth and local invasion [27]. [score:6]
Among these miRNAs, downregulation of miR-141 has been reported in gastric cancer [44] and renal cell carcinoma [45]. [score:4]
In addition to the decrease of let-7a, miR-15a, and miR-16, they also found underexpression of miR-21, miR-141, miR-143, miR-145, and miR-150 in ACTH-secreting pituitary adenomas compared with normal pituitary tissues [27]. [score:2]
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[+] score: 19
Dysregulated miRs in breast CAF included upregulation of miR-221, miR-31, and miR-221 with the downregulation of miR205, miR-200b, miR-200c, miR-141, miR-101, miR-342, let-7g and miR-26b affecting all aspects of cell differentiation and paracrine regulation (Zhao et al. 2012). [score:9]
A related study screening 667 abundant miRs in the serum of prostate cancer patients identified miR-375 and miR-141 to be closely associated with disease progression (ClinicalTrials. [score:3]
This secondary endpoint is supported by a number of previous clinical studies including, one where miR-21, miR-141 and miR-221 was detected in the plasma of a prostate cancer cohort of 51 patients (locally advanced or metastatic) had higher expression compared to 20 healthy controls (Yaman Agaoglu et al. 2011). [score:2]
The secondary outcome of this study is to correlate miR-375 and miR-141 to visible efficacy of the radiation therapy. [score:1]
It turned out that miR-21 helped distinguish between healthy and prostate cancer patients, but miR-141 (miR-200 family member) enabled distinction between localized and metastatic subjects. [score:1]
The study therefore proposed that circulating miR-375 and miR-141 can be used as a non-invasive biomarker for tumor progression (Brase et al. 2011). [score:1]
For those patients that do not manifest a drop in miR-141 with radiation, an anti-miR-141 could be supplemented with radiation. [score:1]
Although in the epithelia miR-205 and miR-200 family members (miR-200c, miR-200b and miR-141) are associated with EMT progression, in fibroblastic cells they clearly have a different function. [score:1]
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[+] score: 19
Another study by Su et al. [12] searched, in a cohort of placentas, the miRNAs that regulate endocrine gland derived vascular endothelial growth factor (EG-VEGF) expression: they concluded that miR-346 and miR-582-3p regulate EG-VEGF -induced trophoblast invasion through repressing metalloproteinases 2 and 9. In addition, FGR placental tissues show an aberrant high expression level of miR-141, suggesting that this miRNA might play important roles in the pathogenesis of the disease by suppressing E2F transcription factor 3 and pleomorphic adenoma gene 1 [13]. [score:11]
In this regard, we acknowledge that it may be extremely important to address future research directions taking into account the already available data from in vitro experiments and animal mo dels: indeed, accumulating evidence suggests that miR141-3p and miR-200a-3p play a pivotal role for placental development in mouse and regulate the expression of insulin-like growth factor 2 [50]. [score:6]
In a small-scale analysis, others found that a group of miRNAs that are altered by hypoxia in trophoblasts (miR-27a, miR-30d, miR-141, miR-200c, miR-424, miR-205 and miR-451, miR-491, miR-517a, miR-518b, miR-518e, and miR-524) is elevated in FGR pregnancies (n = 14 FGR versus n = 14 controls) [47]. [score:1]
Some of these miRNAs, such as miR-141, miR-200c, and miR-205, were studied also in animal mo dels [48, 49]. [score:1]
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[+] score: 19
On day 6, the reporter activity for either miR-200c or miR-141 in Dox+ cells reached similar levels to that of the reporters without the target sequence (untargeted, UT) indicating that RNA interference by either miR-200c or miR-141 had been almost fully suppressed. [score:7]
Importantly, transcription of the miR-200c/141 locus, which is also known to be under direct negative regulation of Zeb1 and Zeb2 11, was also suppressed in the Dox+ cells as judged by the reduction in the pri-miR-200c/-141 transcript level using a primer pair that does not detect mature miR-200c or miR-141. [score:4]
The expression ratios of miR-200c-RL/FL to UT-RL/FL or miR-141-RL/FL to UT-RL/FL are represented by the mean ± SD (n = 3). [score:3]
The hybrid TuD molecule we have designed and described herein, TuD-141/200c, can very efficiently and simultaneously inhibit miR-141 and miR-200c (Fig. 1b,c). [score:3]
In contrast, the activities of miR-200c and miR-141 had almost reverted to their original states by day 27 in the Dox+/− cells (9 days after Dox removal). [score:1]
Considering that the core sequence of miR-200c is shared by miR-200b and -429, whereas that of miR-200a is identical to miR-141 (Fig. 1a), we designed a hybrid type TuD molecule with 2 miRNA binding sites (MBS) that are complementary to miR-200c and miR-141, respectively. [score:1]
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[+] score: 19
However in one dyad, hsa-miR-141-3p was downregulated in post-feed milk compared to pre-feed milk, whereas in another dyad hsa-miR-375 was upregulated in post-feed milk. [score:6]
Suppressor of cytokine signaling (SOCS) protein family is also responsible for termination of GH-activated STAT signaling [68], where the expression of SOCS1-7 proteins is regulated by HM cell miR-182-5p, let-7f-5p, miR-148a-3p, miR-22-3p, miR-16-5p, miR-181a-5p, miR-141-3p (Figure S6). [score:6]
Importantly, most of the highly expressed HM cell miRNA (let-7f-5p, miR-16-5p, miR141-3p, miR30a/d-5p, miR182-5p, andmiR375-3p) regulate the insulin-like growth factor-I receptor (IGF-IR) (Figure S6). [score:4]
All members of the STAT family are controlled by highly expressed HM cell miRNAs, including miR-181A-5P, miR-30a/d-5p, and miR-141-3p. [score:3]
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[+] score: 18
The expression levels of miR-144, miR-141 and miR-214 were negatively correlated with E2F3 level, and overexpression of those miRNAs was found to inhibit proliferation of HCC cells [50, 68, 83]. [score:7]
Studies demonstrated the biological functions of miR-144, miR-141 and miR-217, with the ability to suppress migration and invasion of HCC cells by downregulating E2F3 [50, 51, 68]. [score:6]
miR-141 was observed to be significantly decreased in both HCC tissues and cell lines and E2F3 was identified as its direct target [68]. [score:4]
The miR-200 family, composed of four members (miR-200a, miR-200b, miR-200c, miR-141 and miR- 429), has been reported to play roles in various celluar processes, such as growth, migration, invasion and chemoresistance [9]. [score:1]
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[+] score: 18
Recent studies demonstrated that miR-141 is mainly expressed in the reproductive system, and gradually decreased during male germ cell development and in neonatal spermatogonia [48], [49]. [score:4]
Another study also detected up-regulation of miR-141 and -429 in seminal plasma of non-obstructive azoospermia patients compared with fertile controls. [score:3]
It was noticeable that miR-200 family members including miR-200a/b/c and their star sequences, miR-141 and miR-429/429a/429b all have a male-biased expression. [score:3]
Expression of several miR-200 family members, such as miR-141 and miR-429 were lower in YY testis than in XY testis. [score:3]
The expression profile of miR-141 and miR-429 was inversely associated with their methylation status [51]. [score:3]
All above data suggested that miR-141 and -429 are correlated with normal testis development and spermatogenesis in human. [score:2]
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[+] score: 18
For example, miR-141 has been reported to be significantly up-regulated in blood vessels of prostate cancer patients [9]. [score:4]
MiR-141, 5′-(UAA CAC UGU CUG GUA AAG AUG G)-3′, miR-143, 5′-(UGA GAU GAA GCA CUG UAG CUC)-3′, miR-21, 5′-(UAG CUU AUC AGA CUG AUG UUG A)-3′, miR-16, 5′-(UAG CAG CAC GUA AAU AUU GGC G)-3′, miR-92a, 5′-(UAU UGC ACU UGU CCC GGC CUG U)-3′ and cel-miR-39, 5′-(UCA CCG GGU GUA AAU CAG CUU G)-3′ were used as the target sequences. [score:3]
Synthesized miR-141 was also used as an external control for the conditioned medium (final concentration 10 pM) because the concentration of miR-141 in the medium was less than 15 fM. [score:1]
In brief, 100 µl of conditioned medium or PBS buffer (137 mM NaCl, 2.7 mM KCl, 10 mM Na [2]HPO [4], 1.76 mM KH [2]PO [4], pH 7.4), was spiked with 1 µl of 1 nM synthesized miR-141. [score:1]
This is thought to be due to miR-143 contamination or/and cross-hybridization between spiked-in miR-141 and the TaqMan probes for miR-143. [score:1]
If this method is applied to miR-141 and miR-200a, C-probe-141 becomes different from C-probe-200a because it is complementary to the 3′ side of miR-141, which has two nucleotides that are different from miR-200a. [score:1]
However, miR-141 is highly homologous to miR-200a with only two 3′ nucleotide differences (Figure 3B). [score:1]
To distinguish miR-141 from miR-200a, Alexa532-labeled D-probe-200a-(8) and Alexa647-labeled D-probe-141-(8) were added together to the reaction. [score:1]
The Alexa532-labeled D-probe-200a-(8) signal in the presence of miR-141 was 0.69% of the signal in the presence of miR-200a, while the signal of Alexa647-labeled D-probe-141-(8) in the presence of miR-200a was 0.58% of the signal with miR-141 (Figure 3B). [score:1]
The concentration of synthetic miR-141, which was spiked in all media before purification, was used to correct for any variability of miR-143 detection. [score:1]
Surprisingly, PBS buffer with miR-141 showed a very small miR-143 signal of ∼0.0015 pM. [score:1]
For miR-141, C-probe-141-(14), p-5′-(ACC AGA CAG TGT TA A CAA CAA CAA CAA CAA CAA CA)-3′-(6-FAM)-SH and D-probe-141-(8), p-5′-(CTC AAC TGG TGT CGT GGA(-Alexa647) GTC GGC AAT TCA GTT GAG CCA TCT TT ) -3′ were prepared. [score:1]
Two nucleotides of the miR-200a sequence are different from those of miR-141 (red characters). [score:1]
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[+] score: 17
So, we selected the union of the target genes of hsa-miR-141 and hsa-miR-200b for tumor-preferring miRNAs, and the union of the target genes of hsa-miR-22, hsa-miR-125b, and hsa-miR-99a for normal-preferring miRNAs. [score:5]
Click here for file The enriched pathway of the target gene union of hsa-miR-141 and hsa-miR-200b (tumor-preferring). [score:3]
Studies have identified that the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) is overexpressed in breast cancer, promoting breast cancer metastasis and drug resistance [25, 52]. [score:3]
The target genes of hsa-miR-141 and hsa-miR-200b were significantly enriched in the MAPK pathway (p = 2.1E-6). [score:3]
The enriched pathway of the target gene union of hsa-miR-141 and hsa-miR-200b (tumor-preferring). [score:3]
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[+] score: 17
PTEN participates in two overlaps and targets hsa-miR-106b, hsa-miR-141, hsa-miR-17, hsa-miR-21, hsa-miR-26a and hsa-miR-494 whilst simultaneously being targeted by them. [score:5]
Hsa-miR-141 is targeted by three genes and is regulated by two genes. [score:4]
ZEB1 regulates hsa-miR-141, hsa-miR-200c, hsa-miR-34a, hsa-miR-34b and hsa-miR-429 expression. [score:4]
In the associated network, ZEB1 regulates hsa-miR-141, hsa-miR-200c, hsa-miR-34a, hsa-miR-34b, hsa-miR-429 and hsa-miR-141. [score:2]
The second class of miRNA possessed five types of adjacent nodes, including hsa-miR-141. [score:1]
ZEB1 forms self-adaption associations with hsa-miR-141, hsa-miR-200c and hsa-miR-429. [score:1]
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61
[+] score: 17
The top most highly expressed miRNAs in ERBB2 overexpressing cell lines included hsa-let-7b, hsa-miR-640, hsa-miR-200c, hsa-miR-378, hsa-miR-141, hsa-miR-196a, hsa-miR-29c, and hsa-miR-18a*, whereas hsa-miR-501-5p, hsa-miR-202, hsa-miR-760, and hsa-miR-626 were more highly expressed in luminal cell lines lacking ERBB2 overexpression (fold change ≥ 1.5) (see Table S8 in Additional file 1). [score:9]
Notably, however, five of these six miRNAs (hsa-miR-141, hsa-miRNA-26a, hsa-miR-29c, hsa-miR-148b, hsa-miR-193a-3p) showed significantly higher expression in both ER -positive cell lines and primary tumors, and one miRNA (hsa-miR-532-3p) showed significantly lower expression in both ER -positive cell lines and ER -positive tumors (see Table S4B in Additional file 1). [score:5]
Another group of 17 miRNAs (hsa-miR-575, hsa-miR-155, hsa-miR-26b, hsa-miR-200a, hsa-miR-200b, hsa-miR-141, hsa-miR-200c, hsa-miR-190b, hsa-miR-492, hsa-miR-640, hsa-miR-196a, hsa-miR-29c, hsa-miR-93, hsa-miR-193a-3p, hsa-miR-191, hsa-miR-26a, hsa-miR-182) showed significantly higher expression in the major cluster compared with the other miRNAs (fold change ≥ 1.5) (Figure 2, bottom red box). [score:2]
Importantly, this signature includes all four members of the hsa-miR-200 family (hsa-miR-200a, hsa-miR-200b, hsa-miR-200c, hsa-miR-141), hsa-miR-155, and hsa-miR-622 miRNAs. [score:1]
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62
[+] score: 17
Other miRNAs from this paper: hsa-mir-205, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a
ZEB1 knock-down in EPT1B8 cells was additionally associated with specific re -expression of miR-141 and miR-200c, but neither with re -expression of other miR-200 family members nor with re -expression of miR-205 (Table S12), consistent with previous studies in different mo dels [30]. [score:8]
Following ZEB1 knock-down miR-141 and miR-200c were found to be re-expressed in EPT1B8 cells on the average to 14.4% and 13.2%, respectively, of EP156T expression levels (Figure S4D). [score:6]
d. (D) miR-141 and miR-200c expression in EPT1B8 cells following ZEB1 knock-down compared to levels in EP156T cells. [score:3]
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63
[+] score: 16
[179] In addition, some non-BMP-regulated miRNAs also have regulatory roles in BMP signaling: miR-141 and -200a remarkably modulate the BMP-2 -induced pre-osteoblast differentiation through the translational repression of Dlx5; [180] miR-542-3p targets BMP7 and represses BMP7 -induced osteoblast differentiation and survival; [181] miR-20a promotes osteogenic differentiation through upregulation of BMP/Runx2 signaling by targeting PPARγ, Bambi, and Crim1; [182] miR-140 targets a mild inhibitor of BMP Dnpep, and loss of miR-140 in mice causes growth defects of endochondral bones and craniofacial deformities. [score:16]
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64
[+] score: 16
Moreover, HOTAIR inhibits miR-34a expression in prostate cancer [17], miR-331-3p expression in gastric cancer [18] and miR-141 expression in renal carcinoma cells [19]. [score:9]
HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer [18], and is targeted and regulated by miR-141 in human renal carcinoma cells [19]. [score:7]
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65
[+] score: 15
Moreover, Bmi-1 transcriptionally down-regulates miR-141 and miR-200c completing an autoregulatory loop necessary for maintaining tissue homeostasis [104]. [score:5]
However, miR-141 and miR-200c, which belong to miR-200 family, have been demonstrated to directly target Bmi-1 [71, 102, 103]. [score:4]
Indeed, it displays a seed sequence for miR-200a and is a demonstrated target of miR-141, a miR-200 family member that posses the same seed sequence of miR-200a. [score:3]
miR-141, which possesses the same seed sequence of miR-200a, induces senescence in human fibroblasts via posttranscriptional regulation of Bmi-1 [71]. [score:2]
The miR-200 family consists of five members that can be divided into two functional groups according to their seed sequences: miR-200b, miR-200c, and miR-429 belong to functional group I whereas miR-141 and miR-200a to functional group II [69]. [score:1]
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66
[+] score: 15
miR-200a and miR-429 were significantly downregulated, but no changes were observed in abundance of miR-200c and miR-141 ** P < 0.01, Student’s t-test, Data represent mean ± SEM of at least four independent experiments. [score:4]
Moreover, miR-200c and miR-141, which are transcribed independently, are expressed normally suggesting that there are no compensatory effects. [score:3]
The expression of miR-200c and miR-141 did not change in the miR-200b [−/−] lungs compared to miR-200b [+/+] lungs, suggesting that there were no compensatory effects on other family members (Fig.   1f and Supplementary Fig. 5). [score:2]
The expression of miR-200c and miR-141 did not change in the miR-200b [−/−] fetal lungs compared to miR-200b [+/+] lungs, suggesting that there were no compensatory effects on other family members. [score:2]
MiR-200b belongs to the miR-200 family (miR-141, miR-429, miR-200a, miR-200b and miR-200c) and regulates epithelial-to-mesenchymal transition (EMT) in cancer and organ fibrosis 17– 20. [score:2]
Like what we observed in fetal lungs, adult miR-200b [−/−] lungs had lower miR-200ba and miR-429 abundance, but no changes in miR-200c and miR-141 abundance (Supplementary Fig. 5). [score:1]
Although miR-200c has the exact same seed sequence as miR-200b, the abundance of this microRNA along with miR141 was not changed in lungs and kidneys of 8-week old miR-200b [−/−] mice suggesting the absence of any compensatory effects of these two miR-200 family members in miR-200b deficient mice. [score:1]
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67
[+] score: 15
Our results showed that miR-200b, c and 429 mainly target site I and II, whereas miR-141, 200a mainly target site III (Figures 1D–F). [score:5]
Among them, miR-200a/b/c, miR-141, and miR-429 in the miR-200 family were significantly upregulated in early age AD in mice. [score:4]
As predicted by Targetscan (version 6.2, 2012), three miR-200 family bind sites (Site I and Site III for miR-141/200a, Site II for miR-200b/c/429) are highlighted. [score:3]
MiR-200 family can be divided into two groups according to the seed sequences (group I: miR-141 and miR-200a; group II: miR-200b, miR-200c, and miR-429). [score:1]
pMIR-Reporter constructs containing either wild type or mutant fragments of PTEN 3′UTR were co -transfected into 293T cells with miR-200 family miRs (miR-141/200a, miR-200b/c/429, or miR-200c). [score:1]
Name of miRs/siRNAs Sequence miR-200a 5′-UAACACUGUCUGGUAACGAUGU miR-200b 5′-UAAUACUGCCUGGUAAUGAUGA miR-200c 5′-UAAUACUGCCGGGUAAUGAUGGA miR-141 5′-UAACACUGUCUGGUAAAGAUGG miR-429 5′-UAAUACUGUCUGGUAAUGCCGU miR-NC 5′-UAACGUGUCACGUCUCCGACUA Anti-miR-200c 5′-UAACACUUGCCGGGUAAUGGUGUA Anti-miR-NC 5′-UCUUGCCGGGCCCGAUCCAACGA siCont 5′-UUCUCCGAACGUGUCACGU siPTEN 5′-AACCCACCACAGCUAGAACUU 2.3 kb PTEN 3′UTR was amplified by PCR from a human cDNA library. [score:1]
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68
[+] score: 15
For example, miR-138 modulates metastasis and EMT in breast cancer cells by targeting vimentin [7], miR-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes [47], miR-141 downregulates the expression of vimentin in renal tubular epithelial cells [48], and miR-200c suppresses vimentin [49, 50]. [score:11]
The following factors were confirmed to modulate vimentin expression: (1) non-coding RNA in the regulation of transcription, such as miR-135a, miR-137, miR-200c, miR-141, miR-122 and long non-coding RNA [5– 11]; (2) protein modification, such as phosphorylation and acetylation [12– 15]. [score:4]
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69
[+] score: 15
miR-193, -30b, -30c, -26a, and -26b are highly expressed during early development, gestation and late involution; miR-141, -200a, -148a, and -146b are highly expressed during gestation, lactation, and early and late involution. [score:6]
miR-141 inhibits EMT in part through targeting of transforming growth factor-β2. [score:5]
Thus, expression of miR-141, -200a and -200b in luminal tumors is in keeping with maintenance of the luminal phenotype. [score:3]
Several of the miRNAs that we have identified as being specific for the luminal-type GEM tumors (miR-141, -200a and -200b) have been shown to repress an EMT [39- 41]. [score:1]
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70
[+] score: 15
Recently, the miR-200 family (miR-141, -200a, -200b, -200c, and -429) and miR-205 have been demonstrated as EMT-suppressive miRNAs directly targeting ZEB1 and ZEB2 [17]. [score:6]
EMT-suppressive Effects of miR-655 on Mesenchymal-like Cancer Cells having Phenotypic Plasticity at EMT/METThe expression profile of miR-655 was compared with that of each of seven typical EMT-related genes (CDH1/E-cadherin, miR-141, -200a, -200b, -200c, -205, and VIM) in a panel of 23 pancreatic cancer cell lines and a breast cancer cell line, MDA-MB-231 (Fig. 2A and Fig. S2). [score:4]
Figure S2Expression profiles of known EMT-related genes, miR-141, -200a, -200b, -200c, -205 and VIM, in a panel of 23 pancreatic cancer cell lines and a breast cancer cell line, MDA-MB-231 (see Fig. 2A and 4A). [score:3]
The expression profile of miR-655 was compared with that of each of seven typical EMT-related genes (CDH1/E-cadherin, miR-141, -200a, -200b, -200c, -205, and VIM) in a panel of 23 pancreatic cancer cell lines and a breast cancer cell line, MDA-MB-231 (Fig. 2A and Fig. S2). [score:2]
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71
[+] score: 14
- In, up-regulation is shown for miR-19a (position 5), miR-183 (position 9), and miR-141 (position 10); we also observe that miR-182 (position 3) is likely to be a true positive. [score:4]
The test considers three sets of miRs: 5 miRs from the 18 targets that were predicted by both HuMiTar and PicTar, i. e. miR-19a, miR-127, miR-141, miR-182, and miR183. [score:3]
The test considers three sets of miRs: 5 miRs from the 18 targets that were predicted by both HuMiTar and PicTar, i. e. miR-19a, miR-127, miR-141, miR-182, and miR183. [score:3]
5 miRs from the 18 targets that were predicted by both HuMiTar and PicTar, i. e. miR-19a, miR-127, miR-141, miR-182, and miR183. [score:3]
The Septin7 expression levels were measured (left to right) for (1) control sample, (2) miR-127, (3) miR-182, (4) miR-412, (5) miR-19a, (6) miR-453, (7) miR-448, (8) miR-450, (9) miR-183, (10) miR-141, (11) miR-202, (12) miR-148, (13) miR-106b, (14) miR-134, (15) miR-106, (16) miR-144, (17) miR-151, (18) miR-384, (19) miR-101, (20) miR-142, (21) miR-129 and (22) miR-126. [score:1]
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72
[+] score: 14
According to our SSH data, miR141, miR21, and miR29C are down-regulated, and miR205 is up-regulated (online Dataset 1, http://small. [score:7]
However, for two miRNAs (miR141 and miR205), contradictory data were reported [up-regulation in Billerey et al. (2001); Aravin et al. (2008); down-regulation in Adachi et al. (2011)]. [score:7]
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73
[+] score: 14
Recently, it was shown that miR-141 downregulates the expression of TGF β2 [71] which shows reduced expression in CC [72]. [score:8]
In numerous cancers, including CC, miR-141 is also overexpressed (Table 1) [43, 68– 70]. [score:3]
This suggests that the overexpression of miR-141 in the cervical epithelium could therefore contribute to cervical tumorigenesis (Figure 1). [score:3]
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74
[+] score: 14
The study revealed that 10 dysregulated miRNA signature among which hsa-miR-1271-5p and hsa-miR-574-3p were down-regulated; and hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-182-3p, hsa-miR-141-5p, hsa-miR-15b-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p were overexpressed in ovarian cancer tissues. [score:7]
In contrast, other miRNAs such as miR-182-5p, miR-183-5p, miR-96-5p, miR-15b-5p, miR-182-3p, miR-141-5p, miR-130b-5p, and miR-135b-3p had a significantly higher expression level in ovarian cancer tissue sample group (C group) than in the normal group (P values are presented in Table 2). [score:3]
Not just miR-141, we further found that other members (200a/b/c) of miR200 family are also overexpressed in EOC comparing to the normal (Table 3). [score:3]
Among these miRNAs, miR-96, miR-182 and miR-183 are clustered at one locus of the chromosome 7 [17] and miR-141-5p belongs to the miR-200 family, which is clustered on the chromosomes 12. [score:1]
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75
[+] score: 14
Regarding the number of target mRNAs; miR-944, miR-141-3p, and miR-203a ranked top three among down-regulated miRNAs, while miR-140-3p, miR-452-5p, and miR-137 located top three of up-regulated miRNAs (Figure 1). [score:9]
Consistent with previous reports [10, 11], miR-10b-5p (miR-10b) and miR-224 were overexpressed, miR-200c-3p (miR-200c) and miR-141-3p (miR-141) were significantly reduced in NSCLC cell lines, and our laboratory also reported reduced expression of miR-129-1-3p and miR-203a in the NSCLC sample [12, 13]. [score:5]
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76
[+] score: 14
Other miRNAs from this paper: hsa-mir-200b, hsa-mir-200c, hsa-mir-200a, hsa-mir-429
miR141 was downregulated in HKC-8 cells but not in hPTECs. [score:4]
Compared to miR200b, which was used as reference in Fig. 5C, miR200c and miR141 were expressed less abundantly with a considerably higher expression in hPTECs compared to HKC-8 cells. [score:3]
Nevertheless, the biological significance remains to be determined as miR141 had by far the lowest expression level. [score:3]
Given the selective regulation of miR141, a role of further members of the miR200 family, e. g. miR200a or miR429 cannot be excluded. [score:2]
In HKC-8 cells, miR141 was reduced by 25%. [score:1]
Error bars of miR200c and miR141 in HKC cells were smaller than the line thickness of the graph. [score:1]
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77
[+] score: 13
MiR-223 and miR-141 suppressed ICAM-1 expression in EC cultures in vitro [40, 41], while NF-κB mediated inflammation was regulated by elevated expression of miR-146a and miR-155 [25, 39]. [score:8]
In other experiments, TNF-α treatment in HUVECs resulted in decreased miR-141 levels causing enhanced ICAM-1 expression [41], while miR-149 was also decreased due to the same response affecting IL-6 and metalloproteinase-9 expression in EC cultures [38]. [score:5]
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78
[+] score: 13
Epigenetic modification Cell lines or biological samples (location) Assessment/modification Identified gene targets Dose (range) DNA methylationBlood (San Francisco, USA, n = 58) Targeted/hypermethylation GSTM1 Blood Hg: 2.9 μg/LHanna et al., 2012 DNA methylationBuccal mucosa samples (Michigan, USA, n = 131) Targeted/hypomethylation SEPP1 Hair Hg: 0.31–0.44 (μg/g)Goodrich et al., 2013 Urine Hg: 0.60–0.83 (μg/L) mi -RNA NT2 (carcinoma pluripotent stem cells) Genome-wide/ – 400 nM MeHgCl for 2–36 dPallocca et al., 2013 ↑ miR-302b ↑ miR-367 ↑ miR-372 miR-196bmiR-141↑, increased; ↓, decreased; [*], functionally validated at the expression level; –, not functionally validated at the expression level; Global refers to global methylation patterns; Genome-wide refers to high throughput gene-specific assays; DMGs, differentially methylated genes. [score:10]
In carcinoma pluripotent stem cells, exposure to methyl mercury chloride (MeHgCl) was associated with increased expression of miR-302b, miR-367, miR-372, miR-196b, and miR-141 (Pallocca et al., 2013). [score:3]
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79
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The top five differentially upregulated miRNAs in LGDN (Table  2) were: miR-141 (625-fold), miR-101 (208-fold), miR-22 (111-fold), miR-16 (61-fold), and miR-486 (35-fold); whereas, the top five downregulated were: miR-451a (513-fold), miR-378c (104-fold), miR-361 (95-fold), miR-122 (81-fold), and miR-30c (78-fold). [score:7]
In cirrhosis, 16 miRNAs were dysregulated whereas four were dysregulated in LGDN (let-7d, miR-141, miR-181b, and miR-3120), none in HGDN, miR-150 in eHCC, and 29 in HCC. [score:3]
LGDN was most defined by changes in miR-141(626-fold) and piR-25782.5 (309-fold), while piR-25782.1 (181-fold) was expressed in HGDN. [score:3]
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80
[+] score: 13
Summary of gene lists generated from random controls (predicted targets of miR-141/146b/216 and first and second sets of 17 random genes) and 11 TGF-beta pathway genes from predicted targets of miR-34b/34c/449. [score:5]
Click here for file Summary of gene lists generated from random controls (predicted targets of miR-141/146b/216 and first and second sets of 17 random genes) and 11 TGF-beta pathway genes from predicted targets of miR-34b/34c/449. [score:5]
Three miRNAs, miR-141/146b/216, were randomly chosen and all subsequently procedures followed the same workflow for the miR-34b/34c/449 including prediction of targets, screening of gene symbols and GO categories/terms, union of all selected genes, and clustering analysis of tumor specimens. [score:3]
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81
[+] score: 13
In an example of an RNA virus employing cellular miRNA to selectively disrupt host machinery, the enterovirus EV71 was shown to upregulate cellular miR-141, which binds the 3′UTR of the eukaryotic translation initiation factor 4E (eIF4E) mRNA and downregulates its expression, thereby facilitating virus -mediated switch from cellular to viral translation [173]. [score:13]
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82
[+] score: 12
Nevertheless 5 of our 19 downregulated miRNA in the cancer cell lines and ATC were reported as downregulated in at least one of these studies: let-7f, miR-26a, miR-138 and miR-141. [score:7]
The downregulation of different members of this family (hsa-miR-141, 200a and 200c) in the cell lines and in ATC could thus participate in promoting EMT. [score:4]
Among these modulated miRNA, some are part of the same miRNA families: miR-135a and miR-135b are members of the miR-135 family; miR-200a, miR-200b, miR-200c and miR-141 belong to the miR-200 family; miR-30a and miR-30e to the miR-30 family; and let-7f and let-7g to the let-7 family. [score:1]
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83
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Induction of epithelial-mesenchymal transition and down-regulation of miR-200c and miR-141 in oxaliplatin-resistant colorectal cancer cells. [score:4]
MicroRNA-141 regulates Smad interacting protein 1 (SIP1) and inhibits migration and invasion of colorectal cancer cells. [score:3]
MicroRNA-141 regulates the tumour suppressor DLC1 in colorectal cancer. [score:3]
The miR-200 family consists of miR-200a/b/c, miR-141 and miR-429, which are located in two gene clusters in mice and humans. [score:1]
Specifically, miR-200c and miR-141 have been shown to be elevated in liver metastases relative to levels in primary CRC tumors (Hur et al., 2013). [score:1]
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84
[+] score: 12
Other miRNAs from this paper: hsa-mir-224, hsa-mir-200c, hsa-mir-452, hsa-mir-888, hsa-mir-877
Overexpression of miR-200c, and miR-141, both of which putatively target the BRCA1 associated protein-1 oncosuppressor-encoding BAP1, is correlated with OV tumor growth, dedifferentiation, and invasiveness [50, 51]. [score:7]
All four microRNAs that are differentially expressed between the 6p+12p tensor GSVD classes, and map to the same amplification, miR-200c, miR-200c*, miR-141, and miR-141*, are consistently overexpressed. [score:5]
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85
[+] score: 12
Other miRNAs from this paper: hsa-let-7b, hsa-mir-21, hsa-mir-27a, hsa-mir-148a, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-203a, hsa-mir-1-2, hsa-mir-23b, hsa-mir-122, hsa-mir-126, hsa-mir-146a, hsa-mir-1-1, hsa-mir-155, hsa-mir-34b, hsa-mir-34c, hsa-mir-296, hsa-mir-370, hsa-mir-373, hsa-mir-342, hsa-mir-526a-1, hsa-mir-526a-2, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-542, hsa-mir-548e, hsa-mir-548j, hsa-mir-548k, hsa-mir-548l, hsa-mir-548f-1, hsa-mir-548f-2, hsa-mir-548f-3, hsa-mir-548f-4, hsa-mir-548f-5, hsa-mir-1246, hsa-mir-548g, hsa-mir-548n, hsa-mir-548m, hsa-mir-548o, hsa-mir-548h-1, hsa-mir-548h-2, hsa-mir-548h-3, hsa-mir-548h-4, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-548q, hsa-mir-548s, hsa-mir-466, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-548x, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-548am, hsa-mir-548an, hsa-mir-203b, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-548ay, hsa-mir-548az, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
Hence, virus infection -induced miR-141 expedites the translational switch from cap -dependent translation to cap-independent translation. [score:7]
Ho and his colleagues found that cellular miR-141 is induced by EV71 infection, which targets eIF4E, the cap -dependent translation initiation factor, and results in the shutdown of host protein synthesis, while the silencing of virus infection -induced miR-141 almost recovers host protein synthesis and blocks viral propagation up to 1000-fold [59]. [score:5]
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86
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Zhu et al. described miR-141 as a significant tumor suppressor in pancreatic cancer, as it interferes with the proliferative pathway mediated by Yes -associated protein-1 [11]. [score:3]
Among the subgroup analyses stratified by individual miRNAs, a pooled analysis of the miR-141 subgroup indicated that increased tissue expression was significantly correlated with enhanced OS (pooled HR = 0.38, 95% CI 0.23–0.64), which was determined using a random-effects mo del given the moderate heterogeneity among the studies (P = 0.09, I [2] = 53%; Supplementary Figure  3A). [score:3]
Subgroup analyses also showed that miR-141 and miR-200b were associated with favorable OS, with pooled HRs of 0.40 and 0.58, respectively. [score:1]
The miR-200 family includes five members (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) and can be divided into two clusters based on chromosomal location. [score:1]
MiR-200b, miR-200c, and miR-429 have the same seed region (nucleotides 2–7), and miR-200a and miR-141 share a seed region with a difference in only the fourth nucleotide (U to C) among these regions [6]. [score:1]
The miR-200c/141 cluster is comprised of miR-200c and miR-141 and is located on chromosome 12p13 [5]. [score:1]
org/10.1155/2017/1928021): miR-141, miR-200, or miR-429 combined with prognostic, prognosis, survival, tumor, cancer, neoplasm, or carcinoma. [score:1]
In 258 cases of colorectal cancer [41], high levels of plasma miR-141 were associated with unfavorable OS (HR = 2.40, 95% CI 1.182–4.86). [score:1]
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87
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The miR-200 gene family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) and miR-205 encode key regulators of EMT that act by directly targeting zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2, which are transcriptional repressors that downregulate E-cadherin (CDH1; Gregory et al., 2008; Korpal et al., 2008; Park et al., 2008). [score:8]
Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. [score:4]
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88
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In the up-regulated miRNAs, we found the five miRNAs have both 5p-arm and 3p-arm expression significantly increased (miR-146b, miR-200a, miR-141 miR-192 and miR-194). [score:6]
Some of the up-regulated arm specific miRNAs include miR-182-5p, miR-183-5p, miR-21-5p, miR-141-5p, miR-1307-5p, miR-130b-3p, miR-196b-5p, miR-210-3p, miR-21-3p and miR-141-3p. [score:4]
In some cases, we observed the few miRNAs have contradictory associations in different cancer types, which indicate multiple biological functions for some of the miRNAs, such as miR-141-5p and miR-141-3p, miR-486-5p. [score:1]
There are few miRNA 5p-arm and 3p-arm pairs identified in our study: miR-21-5p and miR-21-3p; miR-141-5p and miR-141-3p; miR-139-5p and miR-139-3p; miR-145-5p and miR-145-3p. [score:1]
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89
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Compared with the negative control (NC) group, the expression of lncRNA-ATB was negatively correlated with the expression level of miR-141-3p (Lei et al., 2017). [score:4]
Yuan et al. (2014) identified that lncRNA-ATB expression is controlled by TGF-β and negatively associated with the miR-200 family, such as miR-429, miR-141, miR-200a, miR-200b, and miR-200c. [score:3]
Cancer type Effects Related genes EMT process, invasion colonization miR-200s, ZEB1, ZEB2, TGF-β STAT3, IL-11Yuan et al., 2014 EMT process, proliferation invasion, metastasis miR-200s, miR-141-3p, ZEB TGF-β2Saito et al., 2015; Lei et al., 2017 EMT process, proliferation invasion E-cadherin, ZEB1 ZO-1, N-cadherinIguchi et al., 2015; Yue et al., 2016 EMT process, growth, invasion, apoptosis migration, trastuzumab resistance miR-200c, ZNF-217 ZEB1Shi et al., 2015 Prostate cancer EMT process, proliferation cyclin E, cyclin D1, p21, p27, PI3K/AKT, ERKXu et al., 2016 Renal cell carcinoma EMT process, apoptosis, migration, Invasion, proliferationXiong et al., 2016 Migration, apoptosis, invasionKe et al., 2017 Glioma Proliferation, growth migration, invasion miR-200a, TGF-β2Ma et al., 2016 Osteosarcoma Proliferation, migration invasion ZEB1, ZEB2 miR-200sHan et al., 2017 Pancreatic cancer Proliferation, migration, invasion miR-200aQu et al., 2016 EMT process, epithelial-mesenchymal transition process; ZEB1/2, zinc finger E-box binding homeobox 1/2; TGF-β, transforming growth factor β; STAT3, signal transducer and activator of transcription 3; IL-11, interleukin-11; ZNF-217, zinc finger protein 217; ZO-1, zonula occludens-1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; ERK, extracellular signal-regulated kinase. [score:2]
TGF-β activated lncRNA-ATB and TGF-β2 was directly combined with mir-141-3p. [score:2]
Western blot analysis showed that lncRNA-ATB and miRNA (such as miR-141-3p) could act as competitive endogenous RNAs for TGF-β2 and promote tumor progression. [score:1]
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Other miRNAs from this paper: hsa-mir-205, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a, hsa-mir-429
It was also noted that MCAS cells showed predominant overexpression of miR200c, miR141 and miR205 when compared with other cell lines (Figure 4A), which might maintain the expression of E-cadherin and concomitant suppression of TGFβ signaling in a tightly regulated network that includes several negative feedback loops [47], a perturbation in the E-cadherin mRNA expression in the knockdown experiment might result in large MCAS spheroids in Matrigel (Figure 5B). [score:10]
In contrast to these three miRNAs, the patterns shown by miR200c, miR141, and to a lesser extent by miR205, are obviously different. [score:1]
The miR200a, miR200b, and miR429 are clustered in chromosome 1p36, and miR200c and miR141 are clustered in chromosome 12p13 [26]. [score:1]
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91
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Furthermore, in silico analysis demonstrated that miR-23b, miR-24-2, miR-141, and miR-449 act as tumour suppressors by inhibiting translation of CTNNB1 mRNA, while miR-150 was proposed to be acting as an oncomiR by modulating adenomatous polyposis coli (APC) [134]. [score:7]
One of the interesting findings of the paper is that, in tumours harbouring CTNNB1 mutation, there was downregulation of miR-16 and miR-141. [score:5]
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92
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For instance, downregulation of miR-141 increases CUL3 expression in Hirschsprung's disease [49], and miR-19 targets CUL5 to regulate proliferation and invasion of cervical cancer cells [50]. [score:11]
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93
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Meanwhile, ZEB1 can directly suppress miRNA-200 family members in cancer cells, including miR-141 and miR-200c [36, 37]. [score:4]
Members of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) have emerged as important regulators of EMT, in part by targeting ZEB1 and ZEB2. [score:4]
MiRNAs that inhibit EMT, such as miR-141, were found in the circulation of patients with metastatic colon cancer, and high levels of plasma miR-141 were predictive of poor survival [122]. [score:3]
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94
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Other miRNAs from this paper: hsa-mir-34a, hsa-mir-200b, hsa-mir-200c, hsa-mir-200a
To address this point, we globally analysed the expression of miRNAs in response to palmatine chloride treatment and found that this compound increased a number of tumour-suppressor miRNAs, including miR-34a and miR-141 (Supplementary Fig. S1). [score:5]
In addition, miR-141 strongly suppresses cancer cell migration and invasion by reducing TGFβ2 16. [score:3]
For instance, we found that palmatine chloride treatment increased the tumour-suppressor miRNAs miR-34a and miR-141 in MCF7 cells (Supplementary Fig. S1). [score:3]
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95
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-17, hsa-mir-19a, hsa-mir-21, hsa-mir-31, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-105-1, hsa-mir-105-2, hsa-mir-199a-1, hsa-mir-34a, hsa-mir-187, hsa-mir-199a-2, hsa-mir-205, hsa-mir-214, hsa-mir-221, hsa-let-7g, hsa-let-7i, hsa-mir-128-1, hsa-mir-144, hsa-mir-145, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-146a, hsa-mir-200c, hsa-mir-128-2, hsa-mir-29c, hsa-mir-376a-1, hsa-mir-378a, hsa-mir-133b, hsa-mir-429, hsa-mir-487a, hsa-mir-515-1, hsa-mir-515-2, hsa-mir-526b, hsa-mir-514a-1, hsa-mir-514a-2, hsa-mir-514a-3, hsa-mir-376a-2, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-656, hsa-mir-542, hsa-mir-378d-2, hsa-mir-548e, hsa-mir-548j, hsa-mir-548k, hsa-mir-548l, hsa-mir-548f-1, hsa-mir-548f-2, hsa-mir-548f-3, hsa-mir-548f-4, hsa-mir-548f-5, hsa-mir-548g, hsa-mir-548n, hsa-mir-548m, hsa-mir-548o, hsa-mir-548h-1, hsa-mir-548h-2, hsa-mir-548h-3, hsa-mir-548h-4, hsa-mir-1275, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-2114, hsa-mir-548q, hsa-mir-548s, hsa-mir-378b, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-548x, hsa-mir-514b, hsa-mir-378c, hsa-mir-4303, hsa-mir-4309, hsa-mir-4307, hsa-mir-4278, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-378f, hsa-mir-378g, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-378h, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-378i, hsa-mir-548am, hsa-mir-548an, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-378j, hsa-mir-548ay, hsa-mir-548az, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
The has-miR-2114 was reported to be upregulated, while has-miR-141 and has-miR-146a were downregulated [20]. [score:7]
However, only eight aberrantly expressed miRNAs (including has-miRplus-A1087, has-miR-542-3p, has-miR-141, has-miR-200c, has-miR-214, has-miR-29c, has-miR-378, and has-miR-128) were consistent with our findings. [score:3]
A subset of miRNA reported to associate with H. pylori infection, such as has-miR-141, has-miR-146a, and has-miR-2114, is detected in our study. [score:1]
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For instance, by selecting prostate cancer disease (in step 3 of the tool), for both extracellular and cellular miRNAs, users will see that there is no difference in the expression profile patterns for some miRNAs (e. g. let-7c, let-7e and miR-107), while there are some differences for other miRNA signatures (e. g. miR-141 is up-regulated in the plasma of prostate cancer patients [32], and is down-regulated in prostate cancer cell lines [33]). [score:11]
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97
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It should be noted that other microRNAs potentially regulating CCNE1 protein expression were also significantly changed, including down-regulation of miR-141, miR-16, miR-15a, miR-352, miR-15b and up-regulation of miR-518e, miR-29a, miR-192, and miR-29b, implicating a regulatory network fine-tuning the cell cycle checkpoints. [score:11]
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98
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Mir-517a, mir-141 and mir-517b were down regulated after Hb perfusion in the 10K STBMs. [score:2]
Three miRNAs were down regulated in the 10K STBMs after Hb treatment; mir-517a, mir-141 and mir-517b. [score:2]
After Hb perfusion, mir-517a (p = 0.03671), mir-141 (p = 0.01219) and mir-517b (p = 0.03671) were significantly down regulated in 10K STBMs (Figure 3). [score:2]
All miRNAs (mir-517a, mir-517b, mir-518b, mir-205, mir-210, mir-222, mir-141, mir-16 and mir-424) analysed in this study were present in both 10K and 150K STBMs. [score:1]
To confirm that the differences obtained between the groups were dependent on Hb perfusion, mir-141 and mir-517a were also analysed in phase I, before addition of Hb. [score:1]
In the 10K STBMs mir-517a, mir-141 and mir -517b were significantly down regulated in Hb perfusions compared to controls. [score:1]
Mir-424 and mir-205 are altered in hypoxia [45] and mir-141 in PE [39]. [score:1]
Mir-141 is one of the most abundant miRNAs in the placenta and found in high levels in maternal plasma during pregnancy [52], [53]. [score:1]
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Noteworthily, some of the differentially expressed miRNAs identified in our study during decidualization have been found to be misregulated in endometriosis (e. g., miR-9, miR-135b and miR-141) [56], [17], [43], preeclampsia (e. g., miR-155, miR-183 and miR-181b) [18], [19], [57] or endometrial cancer (e. g., the miR-200 family and miR-96) [54], [58], [59]. [score:4]
This family is located at two different loci (chromosomes 1 and 12) and includes the mir-141, mir-429, mir-200a, mir-200b and mir-200c, miRNAs that were significantly down-regulated in the decidualized hESCs (Figure 1C). [score:4]
These miRNAs share an identical seed region except for miR-141 and miR-200a which change one nucleotide at position 4. The number of shared potential targets was low and was included in the cell cycle pathway. [score:3]
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The miR-141, miR-29 family, miR-96 and miR-106b presented the highest increase in the expression levels (≥ 5 times fold up-regulated). [score:6]
The up-regulated miRNAs in all 21T cell lines, suggesting an early event in tumorigenesis include the oncomiRs miR-29a/b/c [18, 19], miR-141 [20, 21], miR106b [22] and miR-96 [23, 24]. [score:4]
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