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279 publications mentioning hsa-mir-181c (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-181c. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

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[+] score: 387
The microRNA miR-181c has been previously linked with several neurological pathologies, including lipopolysaccharide (LPS) -induced miR-181c downregulation in mice [23], miR-181c downregulation in amyloid β-depositing APP23 transgenic mice and human Alzheimer’s disease tissue [24], middle cerebral artery occlusion -induced miR-181c upregulation in rats [25], and differential miR-181c expression in cerebrospinal fluid samples from multiple sclerosis patients relative to those from other neurologic diseases [26]. [score:16]
Fourth, while MLL1 expression significantly impacts MLL1 -dependent NF-κB target gene expression (i. e., MCP1 and TRAF1) but showed negligible impact upon MLL1-independent NF-κB target gene expression (i. e., SOD2 and TNIP1), miR-181c was able to significantly reduce the expression of all four NF-κB target genes independent of MLL1. [score:15]
This suppression of the inhibitory miR-181c promotes MLL1 expression, increases NF-κB activity, and upregulates downstream NF-κB target gene expression in human microglia. [score:14]
In sum, thrombin -induced, TNF-α/TNFR -dependent miR-181c downregulation promotes MLL1 expression, increases NF-κB activity, and upregulates NF-κB target gene expression in human microglia (Additional file 3: Figure S3). [score:13]
In conclusion, thrombin -induced, TNF-α/TNFR -dependent miR-181c downregulation promotes MLL1 expression, increases NF-κB activity, and upregulates NF-κB target gene expression in human microglia. [score:13]
Thrombin -induced, TNF-α/TNFR -dependent miR-181c downregulation promotes MLL1 expression, increases NF-κB activity, and upregulates NF-κB target gene expression. [score:13]
These combined findings suggest that, although miR-181c negatively regulates MLL1 expression, miR-181c is able to inhibit NF-κB activation and downregulate NF-κB target gene expression through mechanism(s) independent of MLL1. [score:13]
Therefore, we hypothesize that miR-181c acts to suppress NF-κB activation and downregulate NF-κB target gene expression through these other NF-κB -associated signaling pathways. [score:10]
Fig. 2Thrombin -driven, PAR4 -mediated TNF-α expression downregulates miR-181c and upregulates MLL1. [score:9]
Thereafter, we determined that thrombin -induced miR-181c downregulation is TNF-α/TNFR -dependent and that miR-181c directly binds to and negatively regulates mixed lineage leukemia 1 (MLL1) expression. [score:8]
Moreover, the addition of the thrombin-specific proteolytic inhibitor PPACK significantly inhibited thrombin’s effects upon miR-181c or MLL1 expression (Additional file 2: Figure S2). [score:7]
Second, although this study suggests that thrombin -driven PAR4 activity induces significant miR-181c downregulation that is dependent upon TNF-α/TNFR, the precise mechanism by which the TNF-α/TNFR pathway downregulates miR-181c in microglia remains an open question. [score:7]
In sum, under both untreated control and thrombin -treated conditions, MLL1 expression has a significantly positive effect upon MCP1 and TRAF1 expression, while miR-181c significantly reduces MCP1 and TRAF1 expression independent of MLL1. [score:7]
In sum, under both untreated control and thrombin -treated conditions, MLL1 expression has negligible effects upon SOD2 and TNIP1 expression, while miR-181c significantly reduced SOD2 and TNIP1 expression independent of MLL1. [score:7]
As MLL1 and miR-181c levels show an inverse relationship and TargetScan analysis revealed four putative miR-181c binding sites on MLL1’s 3′ UTR (Additional file 1: Figure S1), we hypothesized that miR-181c may directly regulate MLL1 expression in human microglia. [score:7]
Thrombin or PAR4AP -induced miR-181c downregulation (p < 0.05) and MLL1 upregulation (p < 0.05) that were dependent upon TNF-α/TNFR. [score:7]
First, we found that thrombin or PAR4AP induces significant miR-181c downregulation and significant MLL1 upregulation in primary human microglia that are dependent upon TNF-α/TNFR. [score:7]
Both TNF-α as well as MLL1 were found to be upregulated following thrombin treatment (Fig.   2a), and we confirmed inverse relationships between TNF-α and MLL1 expression versus miR-181c levels at 1, 3, 6, and 12 h post-thrombin treatment (Fig.   2a). [score:6]
Third, although we show that miR-181c is capable of negatively regulating NF-κB activity and the expression of NF-κB target genes independent of MLL1, the precise alternative mechanism(s) by which it does so remain unclear. [score:6]
In order to validate that miR-181c directly suppresses MLL1 expression, a dual-luciferase reporter system was used. [score:6]
With specific respect to microglia cells, Zhang et al. discovered that oxygen-glucose deprivation (OGD) significantly downregulates miR-181c expression in rodent microglial cells [18, 27]. [score:6]
Moreover, although we showed that miR-181c binds to and negatively regulates MLL1 expression (Fig.   3), we found that miR-181c inhibited NF-κB activation in microglia independent of MLL1 (Fig.   4c). [score:6]
Several previous studies have shown that miR-181c negatively regulates other key signaling proteins (such as TNF-α) that are able to activate NF-κB and promote expression of its target genes [18]. [score:6]
We found that miR-181c significantly decreased wild-type (but not mutant) 3′-UTR luciferase reporter activity in both microglia (p < 0.05, Fig.   3b) and HEK293T cells (p < 0.05, Fig.   3c), indicating that miR-181c directly suppresses MLL1 expression through binding to its wild-type 3′ UTR. [score:6]
Specifically, treatment with thrombin or PAR4AP was able to induce TNF-α expression and miR-181c downregulation, an effect reversed by anti-TNF-α antibody therapy or TNFR1/2 silencing. [score:6]
Both anti-TNF-α antibodies and TNFR1/2 silencing significantly suppressed thrombin’s (and PAR4AP’s) effects upon miR-181c levels (Fig.   2c) and MLL1 expression (Fig.   2d), with TNFR1/2 silencing having a more pronounced effect than anti-TNF-α antibodies. [score:5]
Second, we found that miR-181c directly binds to and negatively regulates MLL1 expression in microglia. [score:5]
Thrombin treatment increased, while miR-181c reduced, NF-κB activity and NF-κB target gene expression in both wild-type (MLL1+) and MLL1-silenced cells (p < 0.05). [score:5]
TargetScan analysis identified mixed lineage leukemia-1 (MLL1) as a putative gene target for miR-181c. [score:5]
org) was then searched to identify putative human target genes for miR-181c by their 3′ untranslated regions (3′ UTRs). [score:5]
As NF-κB activation has been shown to promote the expression of various pro-inflammatory factors (e. g., TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS)) [27] and we have shown that miR-181c suppresses NF-κB activation in human microglia under thrombin -treated conditions, the current findings suggest that miR-181c mimic therapy may show promise in controlling thrombin -driven microglial activation following ICH. [score:5]
Finally, in order to better understand the roles of miR-181c and MLL1, we analyzed their effects upon nuclear factor kappa-B (NF-κB) activity and NF-κB target gene expression. [score:5]
miR-181c decreased wild-type MLL1 3′-UTR luciferase reporter activity (p < 0.05), and a miR-181c mimic suppressed MLL1 expression (p < 0.05). [score:5]
These combined findings suggest that thrombin -driven PAR4 activity in human microglia promotes TNF-α and MLL1 expression while suppressing miR-181c levels. [score:5]
However, miR-181c significantly reduced the expression of all four of these NF-κB target genes independent of MLL1 (Fig.   5). [score:5]
MLL1 was the highest-ranking target gene that showed a strong relevance to inflammation and immune response (Table  1), and further, TargetScan analysis revealed four putative binding sites for miR-181c on the 3′ UTR of MLL1 (Additional file 1: Figure S1). [score:5]
These combined findings suggest that thrombin -driven PAR4 activity in human microglia promotes MLL1 expression and suppresses miR-181c levels via TNF-α/TNFR. [score:5]
The miR-181c mimic significantly suppressed both MLL1 mRNA and protein expression (p < 0.05, Fig.   3d). [score:5]
Fig. 1Thrombin downregulates miR-181c in human microglia. [score:4]
Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) identified miR-181c as the most significantly downregulated miRNA. [score:4]
Moreover, consistent with Hutchinson et al. ’s work in cultured astrocytes [23], we also showed that this thrombin -induced miR-181c downregulation is dependent upon TNF-α/TNFR (Fig.   2). [score:4]
In sum, the foregoing findings reveal that miR-181c negatively regulates MLL1 expression by binding to its wild-type 3′ UTR. [score:4]
Based on the qRT-PCR findings, miR-181c was found to be the most significantly downregulated microRNA in thrombin -treated microglia cells. [score:4]
Consistent with Zhang et al. ’s findings, we found that thrombin also induced significant miR-181c downregulation in human microglia (Fig.   1b). [score:4]
Under both the untreated control and thrombin -treated conditions, miR-181c significantly reduced SOD2 expression in both wild-type and MLL1-silenced microglia (p < 0.05, Fig.   5c). [score:3]
A dual-luciferase reporter system and miR-181c mimic transfection assessed whether mir-181c directly binds to and negatively regulates MLL1. [score:3]
Thrombin’s proteolytic activity contributed to its effects upon miR-181c and MLL1 expression in human microglia. [score:3]
To generate the miRNA expression vector, the miR-181c gene was amplified from human genomic DNA and then cloned into the pcDNA3.0 vector (Invitrogen). [score:3]
c, d qRT-PCR comparing relative expression levels of c miR-181c and d MLL1 at 3 h following treatment with thrombin or PAR4AP after blocking TNF-α or silencing TNFR1/2. [score:3]
b qRT-PCR comparing relative expression levels of TNF-α, miR-181c, and MLL1 at 3 h following treatment with thrombin, PAR4AP, or PAR1AP. [score:3]
Thrombin -induced TNF-α (via TNFR) suppresses miR-181c levels. [score:3]
Having established the effects of miR-181c and MLL1 upon NF-κB activation, we next analyzed their effects upon NF-κB target genes. [score:3]
Under both the untreated control and thrombin -treated conditions, miR-181c significantly reduced MCP1 expression in both wild-type and MLL1-silenced microglia (p < 0.05, Fig.   5a). [score:3]
In sum, under both untreated control and thrombin -treated conditions, MLL1 expression has a negligible effect upon NF-κB activity, while miR-181c significantly reduces NF-κB activity independent of MLL1. [score:3]
Assessment of MLL1 expression after miR-181c mimic treatment. [score:3]
Four putative binding sites for miR-181c on the 3′-UTR of MLL1 based on the TargetScan search. [score:3]
a qRT-PCR comparing relative expression levels of TNF-α, miR-181c, and MLL1 at 1, 3, 6, and 12 h after 24-h thrombin treatment. [score:3]
In addition, consistent with Zhang et al. ’s findings in rat microglial cells [27], we found that miR-181c also inhibited NF-κB activation in human microglia (Fig.   4a). [score:3]
In order to test this hypothesis, a dual-luciferase reporter system was used to assess whether mir-181c directly binds to and regulates MLL1. [score:3]
Moreover, treatment with the thrombin receptor agonist PAR4AP induced effects similar to thrombin on TNF-α, miR-181c, and MLL1 expression (Fig.   2b), while treatment with another thrombin receptor agonist PAR1AP failed to induce similar effects to thrombin (Fig.   2b). [score:3]
Third, we found that miR-181c was able to negatively regulate NF-κB activity independent of MLL1. [score:2]
As a result, miR-181c was found to be the most significantly downregulated miRNA in thrombin -treated microglia relative to untreated control microglia (Fig.   1b) and was selected for further investigation. [score:2]
Mutations were generated in MLL1’s 3′-UTR sequences complementary to miR-181c’s seed region. [score:2]
After qRT-PCR validation, we then selected the most significantly downregulated miRNA—hsa-miR-181c (hereinafter miR-181c)—for further investigation. [score:2]
Mutations were generated in the MLL1 3′-UTR sequences complementary to the seed region of miR-181c. [score:2]
Further study on the molecular effects of miR-181c across a broader range of brain cells is needed to assess any potential therapeutic benefits for ICH. [score:1]
Microglia cells were transfected with miR-181c mimics or NC. [score:1]
NC-miR indicates the negative control for the miR-181c mimics. [score:1]
A MLL1 3′-UTR fragment containing wild-type or mutated miR-181c -binding sites was cloned downstream of the luciferase reporter gene. [score:1]
Microglia were transfected with miR-181c mimics or NC. [score:1]
Human MLL1 3′-UTR fragments containing either wild-type or mutated miR-181c -binding sites were cloned downstream of the luciferase reporter gene (Fig.   3a). [score:1]
Moreover, under both the untreated control and thrombin -treated conditions, miR-181c significantly reduced NF-κB activity in both wild-type and MLL1-silenced microglia (p < 0.05, Fig.   4c). [score:1]
As miR-181c opposes thrombin’s stimulation of pro-inflammatory NF-κB activity, these findings suggest that miR-181c mimic therapy may show promise in controlling thrombin -driven microglial activation following ICH. [score:1]
Therefore, MLL1 was selected for further investigation as a candidate target gene of miR-181c. [score:1]
d Microglia transfected with miR-181c mimic or NC-miR duplexes. [score:1]
miR-181c’s putative binding sites on MLL1’s 3′-UTR. [score:1]
A synthetic miRNA mimic duplex corresponding to miR-181c—as well as a negative control (NC) RNA duplex for the miRNA mimic duplex—were designed as described previously [18]. [score:1]
As miR-181c opposes thrombin’s stimulation of pro-inflammatory NF-κB activity, miR-181c mimic therapy may show promise in controlling thrombin -driven microglial activation following ICH. [score:1]
a Human MLL1 3′-UTR fragments containing either wild-type or mutated miR-181c -binding sites cloned downstream of the luciferase reporter gene. [score:1]
Then, microglia were transfected with either miR-181c mimic or NC duplexes. [score:1]
TNF-α, miR-181c, and MLL1 mRNA expression levels at 1, 3, 6, and 12 h after thrombin treatment were measured by qRT-PCR. [score:1]
Under both the untreated control and thrombin -treated conditions, miR-181c significantly reduced NF-κB activity in both microglia and HEK293T cells (p < 0.05, Fig.   4a). [score:1]
qRT-PCR was applied to assess tumor necrosis factor-alpha (TNF-α), miR-181c, and MLL1 levels following thrombin or proteinase-activated receptor-4-specific activating peptide (PAR4AP) exposure. [score:1]
Schematic overview of thrombin’s effects upon miR-181c and MLL1 in human microglia. [score:1]
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[+] score: 286
In addition, individual overexpression of these targets potently inhibited the TEAD activity in miR-181c -overexpressing cells (Supplementary Figure 2B), demonstrating that MST1, LATS2, MOB1 and SAV1 were functional effectors of miR-181c on regulating TEAD activation. [score:10]
Expression analysis (left top) and correlation (right) of miR-181c expression and CTGF and BIRC5 mRNA levels, as well as (left bottom) nuclear YAP and TAZ protein expression in 10 freshly collected human pancreatic cancer tissue samples (T). [score:7]
MiR-181c has been found to be upregulated in multiple human cancers, and upregulation of miR-181c contributes to cancer cell proliferation, migration and invasion via different mechanisms [44– 47]. [score:7]
Figure 8Expression analysis (left top) and correlation (right) of miR-181c expression and CTGF and BIRC5 mRNA levels, as well as (left bottom) nuclear YAP and TAZ protein expression in 10 freshly collected human pancreatic cancer tissue samples (T). [score:7]
Consistently, IHC staining results revealed that YAP/TAZ was strongly expressed in pancreatic cancer cells but not in the surrounding stromal cells, and nuclear YAP/TAZ expression correlated with miR-181c expression (Supplementary Figure 7). [score:7]
revealed that miR-181c overexpression significantly suppressed expression levels of MST1, LATS2, MOB1 and SAV1, and phosphorylation levels of downstream effectors YAP (p-YAP [ser127]) and TAZ (p-TAZ [ser89]). [score:7]
Herein, we demonstrated that miR-181c was substantially overexpressed in pancreatic cancer and induced hyper-activation of YAP/TAZ via directly targeting MST1, LATS2, SAV1 and MOB1. [score:6]
Taken together, these findings suggest that miR-181c upregulation promotes pancreatic cancer cell chemoresistance, and inhibition of miR-181c sensitizes pancreatic cancer cells to gemcitabine in vivo. [score:6]
In summary, our study has revealed that miR-181c upregulation plays an important role in pancreatic cancer progression and miR-181c is a critical repressor of Hippo signaling by targeting the core kinase cassette, i. e., MST1, LATS2, SAV1 and MOB1. [score:6]
As shown in Figure 3A and 3B, we found that miR-181c overexpression in pancreatic cancer cells significantly increased, but silencing of miR-181c reduced TEAD -dependent luciferase activity, and expression levels of the Hippo downstream genes CTGF, BIRC5 and BCL2L1 in pancreatic cancer cells. [score:5]
Thus, it would be of great interest to further investigate whether upregulation of miR-181c in pancreatic is attributed to genomic amplification and/or NF-κB -mediated transcriptional upregulation. [score:5]
The expression of miRNA was defined based on the Ct, and relative expression levels were calculated as 2 [−[(Ct of miR-181c) – (Ct of U6)]] after normalisation with reference to expression of U6 small nuclear RNA. [score:5]
As expected, the stimulatory effect of miR-181c on TEAD luciferase activity and expression of CTGF, BIRC5 and BCL2L1 were inhibited by YAP or TAZ silencing (Figure 7D and Supplementary Figure 6B, 6C). [score:5]
C. Kaplan–Meier analysis of 2-year overall survival curves of patients with pancreatic cancer with high miR-181c expression (>median, n = 62) versus low miR-181c expression ( [score:5]
As shown in Figure 4C, cleavages of both caspase 3 and PARP were suppressed in the miR-181c -overexpressing cells treated with gemcitabine. [score:5]
Interestingly, using the publicly available algorithms TargetScan and miRanda, we found that the core components of the Hippo signaling pathway, i. e., MST1, LATS2, MOB1 and SAV1 might be potential targets of miR-181c (Figure 2A). [score:5]
Interestingly, using published microarray–based high-throughput assessment, we found that miR-181c expression was markedly higher in patients with pancreatitis, which was an early event of pancreatic cancer development. [score:4]
Our results revealed that miR-181c upregulation promoted pancreatic cancer cell chemoresistance by inactivating Hippo signaling and subsequently activating YAP/TAZ. [score:4]
In contrast, miR-181c inhibition increased them, suggesting that miR-181c negatively regulated these proteins (Figure 2B). [score:4]
Upregulation of miR-181c correlates with pancreatic cancer progression. [score:4]
Upregulation of miR-181c promotes pancreatic cancer cell chemoresistance in vitro. [score:4]
Upregulation of miR-181c significantly correlated with the clinicopathological features and poorer overall survival of pancreatic cancer patients, suggesting that miR-181c might be associated with the progression of pancreatic cancer. [score:4]
Collectively, our results suggest that miR-181c directly targets MST1, LATS2, MOB1 and SAV1. [score:4]
Clinical relevance of upregulation of miR-181c–mediated Hippo signaling inactivation in pancreatic cancer. [score:4]
Collectively, these results further support the notion that upregulation of miR-181c inactivates the Hippo signaling, and results in poor clinical outcome in pancreatic cancer. [score:4]
Furthermore, luciferase assay showed that miR-181c overexpression attenuated, while inhibition of miR-181c elevated the reporter activities driven by the 3′UTRs of these transcripts (Figure 2C). [score:4]
Figure 4Upregulation of miR-181c promotes pancreatic cancer cell chemoresistance in vitro A. Annexin V-FITC/PI staining of indicated cells treated with gemcitabine (5 μM) for 24 h. B. Representative micrographs (left) and quantification (right) of TUNEL -positive cells following 36-h gemcitabine (5 μM) treatment. [score:4]
Thus, these results suggest that upregulation of miR-181c might be involved in human pancreatic cancer progression. [score:4]
Moreover, cellular fractionation and fluorescent immunostaining assays revealed that overexpression of miR-181c increased nuclear accumulation of YAP and TAZ, while silencing of miR-181c reduced nuclear YAP and TAZ expression (Figure 3C and 3D). [score:4]
In contrast, silencing of miR-181c upregulated MST1, LATS2, SAV1 and MOB1, and reconstituted the Hippo signaling, leading to increased sensitivity to drug -induced apoptosis. [score:4]
Importantly, patients with high miR-181c expression had a significantly poorer overall survival compared to patients with low miR-181c expression (P = 0.001; hazard ratio = 2.03, 95% CI = 1.33–3.11; Figure 1C). [score:4]
Clinical relevance of upregulation of miR-181c– mediated Hippo signaling inactivation in pancreatic cancer. [score:4]
These results suggested that miR-181c promoted gemcitabine resistance and tumor growth, while injection of antagomiR-181c dramatically sensitized PANC-1 cells to gemcitabine treatment and inhibited tumor growth. [score:3]
Meanwhile, the miR-181c locus is located in a region within 19p13 reported to be amplified in different human cancers [47, 50], suggesting that miR-181c overexpression in pancreatic cancer might be associated with genomic amplification. [score:3]
However, ectopic expression of the miR-181c did not exhibit repressive effects on the reporter activities driven by the mutant 3′UTRs of these transcripts within miR-181c–binding seed regions (Supplementary Figure 2A). [score:3]
We exogenously overexpressed miR-181c via miR-181c mimic transfection, and endogeneously silencing miR-181c by transfecting antagomiR-181c (Supplementary Figure 1). [score:3]
D. TEAD transcriptional activity induced by miR-181c was suppressed by YAP or TAZ depletion in the cells. [score:3]
Figure 6Inhibition of miR-181c sensitizes pancreatic cancer cells to chemotherapeutic drugs in vivo A. Xenograft mo del in nude mice. [score:3]
Figure 2 A. Predicted miR-181c target sequence in 3′UTRs of MST1, LATS2, MOB1 and SAV1. [score:3]
Meanwhile, gemcitabine treatment had no effect on miR-181c expression in pancreatic cancer cells (Supplementary Figure 4A). [score:3]
These findings indicate that miR-181c functions as both an oncomir and tumor-suppressive miRNA, depending on the tumor type. [score:3]
A. Predicted miR-181c target sequence in 3′UTRs of MST1, LATS2, MOB1 and SAV1. [score:3]
To investigate the clinical significance and the precise mechanism of action of miR-181c in pancreatic cancer pathogenesis, we examined miR-181c expression in pancreatic cancer samples and found that miR-181c was markedly upregulated in pancreatic cancer tissues as compared to normal tissues. [score:3]
As shown in Figure 8, miR-181c levels in 10 freshly collected pancreatic cancer samples were significantly positively correlated with mRNA levels of the Hippo downstream genes CTGF (r = 0.767, P = 0.010) and BIRC5 (r = 0.795, P = 0.006), as well as nuclear expression levels of YAP (r = 0.762, P = 0.010) and TAZ (r = 0.661, P = 0.038). [score:3]
We further confirmed miR-181c expression in pancreatic cancer tissues using real-time PCR. [score:3]
In the pancreatic cancer samples, statistical analysis revealed that increased miR-181c expression strongly correlated with TNM stage and histological differentiation (all P < 0.05) (Supplementary Table 1 and 2). [score:3]
MiR-181c directly targets the core components of the Hippo signaling pathway. [score:3]
Understanding the precise role of miR-181c in pancreatic cancer pathogenesis and in the Hippo signaling pathway promises to increase our knowledge of the biological basis of cancer development and may also facilitate the development of new therapeutic strategies against pancreatic cancer. [score:3]
D. Fluorescent immunostaining of YAP in the control, miR-181c -overexpressing and miR-181c-silenced PANC-1 cells. [score:3]
In addition, overexpression of miR-181c increased, while silencing miR-181c reduced the binding capability of TEAD1 with CTGF promoter (Supplementary Figure 3). [score:3]
Inhibition of miR-181c sensitizes pancreatic cancer cells to chemotherapeutic drugs in vivo. [score:3]
However, the expression of miR-181c has also been shown to be downregualted in glioblastoma multiforme, and predicted a poor patient survival [48]. [score:3]
Moreover, we also found that neither overexpression of miR-181c nor silencing of miR-181c had an effect on the apoptotic percentage of PANC-1 and BxPC3 cell lines without chemo-drug treatment, suggesting that miR-181c exerted its effects on pancreatic cancer cell survival in the presence of gemcitabine (Supplementary Figure 4C and 4D). [score:3]
Taken together, our results not only suggest miR-181c–induced Hippo signaling inactivation as a novel mechanism for pancreatic cancer chemoresistance; but also propose that miR-181c might be a potential therapeutic target for human pancreatic cancer. [score:3]
Herein, public microarray data and our results together suggested that miR-181c was substantially overexpressed in clinical pancreatic cancer samples and significantly correlated with poor prognosis. [score:3]
Inhibition of miR-181c sensitizes pancreatic cancer cells to chemotherapeutic drugs in vivoThe promotive effect of miR-181c on pancreatic cancer cell chemoresistance was further examined in vivo. [score:3]
As shown in Figure 1B, miR-181c expression was markedly increased in 124 pancreatic cancer samples compared with that in 10 non-cancerous pancreatic tissues. [score:2]
Since resistance of pancreatic cancer cells to chemotherapeutic drugs is crucial for the inefficient therapy, and recent evidence strongly suggests that Hippo pathway inactivation plays important roles in chemotherapeutic drug resistance [8, 11– 15], we then investigated the role of miR-181c upregulation in the drug-resistant survival. [score:2]
B. Real-time PCR analysis of miR-181c expression in 124 freshly collected pancreatic tissues compared to that in 10 non-cancerous pancreatic tissues. [score:2]
MiR-181c inactivates the tumor-suppressive Hippo signaling pathway. [score:2]
miR-181c directly repressed MST1, LATS2, MOB1 and SAV1, leading to YAP/TAZ activation and subsequent promotion of pancreatic cancer cell survival and chemoresistance in vitro and in vivo. [score:2]
Moreover, microribonucleoprotein (miRNP) immunoprecipitation (IP) assay revealed a selective association of miR-181c with MST1, LATS2, MOB1 and SAV1, but not with YAP, TAZ or GAPDH (Figure 2D), further indicating the specific effects of miR-181c on these targets. [score:2]
We synthesised cDNA from 10 ng total RNA using a TaqMan miRNA reverse transcription kit (Applied Biosystems, Foster City, CA, USA), and quantified the expression levels of miR-181c using a miRNA-specific TaqMan MiRNA Assay Kit (Applied Biosystems). [score:2]
Thus, our findings suggest that miR-181c might be involved in the development of pancreatic cancer by inactivating the Hippo signaling. [score:2]
MiR-181c promotes chemoresistance in pancreatic cancer in vitroSince resistance of pancreatic cancer cells to chemotherapeutic drugs is crucial for the inefficient therapy, and recent evidence strongly suggests that Hippo pathway inactivation plays important roles in chemotherapeutic drug resistance [8, 11– 15], we then investigated the role of miR-181c upregulation in the drug-resistant survival. [score:2]
Annexin V and TUNEL assays demonstrated that ectopic expression of miR-181c reduced the apoptosis rate of PANC-1 and BxPC3 pancreatic cancer cells by resisting to the chemotherapeutic agent gemcitabine (Figure 4A and 4B). [score:2]
Moreover, YAP or TAZ silencing abrogated the promotive effects, but overexpression of YAP or TAZ rescued the repressive effects of miR-181c on gemcitabine resistance, as indicated by the TUNEL and colony formation assays (Figure 7E, 7F and Supplementary Figure 6D). [score:2]
Figure 1 A. miR-181c levels remained low in normal pancreatic tissues but became markedly higher in patients with pancreatitis and further elevated in pancreatic cancer patients assessed by analyzing a published microarray (GSE24279; Normal, n = 22; Pancreatitis, n = 27; Pancreatic cancer, n = 136). [score:1]
C. of cells transfected with pGL3-MST1-3′UTR, pGL3-LATS2-3′UTR, pGL3-MOB1-3′UTR or pGL3-SAV1-3′UTR reporter with miR-181c mimic, antagomiR-181c, mimic control or antagomiR control. [score:1]
The promotive effect of miR-181c on pancreatic cancer cell chemoresistance was further examined in vivo. [score:1]
YAP/TAZ activation is essential for miR-181c -induced chemoresistance. [score:1]
B. Silencing of miR-181c increased the number of TUNEL -positive cells following 36-h treatment with gemcitabine (5 μM). [score:1]
Meanwhile, tumors injected with miR-181c mimic had decreased TUNEL -positive apoptotic cells, whereas tumors injected with antagomir-181c had a higher percentage of TUNEL -positive apoptotic cells (Figure 6D). [score:1]
Conversely, the role of miR-181c in pancreatic chemoresistance was further examined by endogenously silencing miR-181c. [score:1]
The mice in groups were inoculated subcutaneously with PANC-1 cells (5 × 10 [6]) in the left dorsal flank, and two weeks later, injected intratumorally with 100 μL miR-181c mimic, mimic control, antagomiR-181c control or antagomiR control (diluted in PBS at 2 mg/mL) three times per week for 4 weeks, combining with intraperitoneal injection of gemcitabine (50 mg/kg) weekly. [score:1]
Moreover, gemcitabine, 5-FU, and paclitaxel treatment significantly reduced the number of colonies formed by the miR-181c–silenced pancreatic cancer cells. [score:1]
Importantly, the colony formation assay indicated that overexpression of miR-181c rendered resistance of pancreatic cancer cells in the presence of gemcitabine, 5-FU, or paclitaxel to form many more colonies as compared to the control (Figure 4D and Supplementary Figure 4B). [score:1]
Finally, we examined whether miR-181c–mediated inactivation of Hippo signaling in pancreatic cancer was clinically relevant. [score:1]
Collectively, these results suggest that miR-181c promotes pancreatic cancer cell resistance to chemotherapeutic drugs in vitro. [score:1]
Each group of mice were intratumorally injected with 200 μg mimic control, miR-181c mimic, antagomir control, or antagomiR-181c (diluted in phosphate-buffered saline [PBS] at 2 mg/ml) three times per week for four weeks, combined with intraperitoneal injection of gemcitabine (50 mg/kg) weekly (Figure 6A and Supplementary Figure 5). [score:1]
Silencing of miR-181c increases chemotherapeutic drug–induced apoptosis of pancreatic cancer cells in vitro. [score:1]
As shown in Figure 5A and 5B, we found that silencing of miR-181c increased the apoptosis rate of PANC-1 and BxPC3 pancreatic cells under the treatment of gemcitabine. [score:1]
Moreover, the effect of miR-181c on apoptotic protection was confirmed by examining the cleavages of pro-caspase 3 and poly (ADP-ribose) polymerase (PARP) in pancreatic cancer cells. [score:1]
Analysis using a published microarray (NCBI/GEO/GSE24279; n = 185, including 22 normal, 27 pancreatitis and 136 pancreatic cancer samples), we found that miR-181c levels remained low in normal pancreatic tissues but became markedly higher in patients with pancreatitis and further elevated in pancreatic cancer patients (Figure 1A). [score:1]
Transfection of the plasmids, siRNAs, miR-181c mimic, and antagomiR-181c were performed using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. [score:1]
B. Tumor volumes of tumors in the miR-181c–overexpressing, miR-181c–silenced, and control groups were measured on indicated days. [score:1]
Of note, by analysis of the promoter region of miR-181c using the CONSITE program, we found two typical response elements of the transcriptional factor nuclear factor κB (NF-κB), which is hyperactivated in pancreatic cancer [49]. [score:1]
were co -transfected with HA-Ago1 together with 100 nM miR-181c, followed by HA-Ago1 immunoprecipitation using HA-antibody. [score:1]
Therefore, our results suggest that miR-181c inactivates the Hippo signaling pathway. [score:1]
Moreover, miR-181c inactivated the Hippo signaling and induced YAP activation. [score:1]
Consistently, cleavages of both caspase 3 and PARP were increased in the miR-181c–silenced cells treated with gemcitabine (Figure 5C). [score:1]
Figure 5Silencing of miR-181c increases chemotherapeutic drug–induced apoptosis of pancreatic cancer cells in vitro A. were treated with gemcitabine (5 μM) for 24 h and stained with annexin V–FITC/PI. [score:1]
We purchased miR-181c mimic, miR-181c antagonist (antagomiR-129-5p), and controls from RiboBio (Guangzhou, China). [score:1]
Consistently, miR-181c dramatically promoted pancreatic cancer cell chemoresistance by inactivating the Hippo signaling pathway, further demonstrating the tumor-promoting role of miR-181c in pancreatic cancer. [score:1]
A. miR-181c levels remained low in normal pancreatic tissues but became markedly higher in patients with pancreatitis and further elevated in pancreatic cancer patients assessed by analyzing a published microarray (GSE24279; Normal, n = 22; Pancreatitis, n = 27; Pancreatic cancer, n = 136). [score:1]
Collectively, these results indicate that activation of YAP/TAZ is critical for miR-181c–induced chemoresistance in pancreatic cancer cells. [score:1]
We further examined the role of miR-181c in Hippo signaling pathway. [score:1]
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[+] score: 257
Furthermore, to understand whether miR-181c overexpression induces differentiation mainly by regulating CARM1 expression, we co -transfected miR-181c mimics and a CARM1 miRNA-resistant expression vector into undifferentiated hESCs and found that co -expression of CARM1 and miR-181c maintained the number of AP -positive colonies independent of the expression of miR-181c (Figure 3C), CARM1 protein expression is also shown (Figure 3C). [score:14]
To further assess the effect of miR-181c on hESC differentiation, we knocked down miR-181c using a specific inhibitor and found that CARM1 and H3R17me2 protein expression levels were clearly down-regulated in comparison to hESCs treated with NC RNA (Figure 4A). [score:9]
Enforced expression of miR-181c led to a clear down-regulation of CARM1 expression at the protein level (Figure 3A). [score:8]
0053146.g004 Figure 4(A) Enforced expression of the miR-181c inhibitor down-regulated mature miR-181c levels relative to negative control (NC) RNA -transfected ESCs, as shown by qRT-PCR. [score:8]
ChIP was performed on sonicated chromatin from wild-type ES cells, CARM1- overexpressing cells, miR-181c -overexpressing cells and cells treated with the miR-181c inhibitor using anti-CARM1, anti-histone H3R17di-me antibodies, anti -RNA Polymerase antibodies and control IgG antibodies. [score:7]
Overexpression of miR-181c promoted the differentiation of hESCs, whereas overexpression of miR-181c inhibitor impeded differentiation. [score:7]
The depletion of CARM1 and histone H3R17 di-me at the promoters of pluripotency genes in miR-181c -overexpressing hESCs reveals that enforced expression of miR-181c induces differentiation independent of BMP4 by targeting CARM1. [score:7]
We found that CARM1 and histone H3R17 di-me were significantly enriched at the promoters of Oct4 and Sox2 in both NC RNA/pcDNA3 -overexpressing hESCs and CARM1 -overexpressing hESCs, whereas this enrichment was clearly decreased in miR-181c -overexpressing hESCs. [score:7]
We also found that CARM1 was post-transcriptionally regulated and was directly targeted by miR-181, which represses the 3′ untranslated region (3′UTR) of CARM1 in hESCs. [score:7]
Unexpectedly, the Nanog promoter did not show any detectable enrichment in NC RNA/pcDNA3 -overexpressing hESCs or miR-181c -overexpressing hESCs, but we found that CARM1 and histone H3R17 di-me were significantly enriched at the Nanog promoter in CARM1 -overexpressing hESCs (Fig. 3F). [score:7]
In differentiated hESCs, H3K27 methylation is inhibited because of the reduction of core pluripotency factors, and miR-181 family members are consequently significantly induced and down-regulate CARM1 activity. [score:6]
In this context, we scanned for microRNAs that target CARM1 and finally identified the miR-181 family as the critical regulator of CARM1 expression. [score:6]
In differentiated hESCs, H3K27 methylation is inhibited due to the reduction of core pluripotency factors, and miR-181 family members are subsequently induced and down-regulate CARM1 activity. [score:6]
To further investigate whether CARM1 directly targets the pluripotency genes Oct4, Sox2 and Nanog, we performed ChIP analysis on wild-type hESCs, miR-181c- overexpressing hESCs and CARM1 -overexpressing hESCs as well as hESCs transfected with negative control (NC) RNA or pcDNA3. [score:6]
Taken together, these results show that miR-181 directly regulates CARM1 by targeting its 3′UTR and that miR-181c may play a prominent role among the 4 members during hESC differentiation. [score:5]
hESCs treated with miR-181c inhibitor expressed Nanog after 8 days of differentiation (C). [score:5]
Figure S3 ChIP analysis of hESCs after miR-181c, CARM1 and miR-181c inhibitor overexpression. [score:5]
Enforced Expression of miR-181c Suppresses CARM1 -mediated Nanog Transcription. [score:5]
Enforced Expression of miR-181c Induced hESC Differentiation by Targeting CARM1 We selectively transfected miR-181c mimics in undifferentiated hESCs to study the effect of miR-181 on hESCs differentiation. [score:5]
Although the miR-181 family also regulates many target genes [21], [46], [47], [48], [49], it is important to highlight that in mouse ESCs, the miR-181 family regulates another histone modulator, Cbx7, which plays a critical role in maintaining ESC pluripotency [50]. [score:5]
The miR-181c inhibitor suppresses hESC differentiation. [score:5]
Enforced Expression of miR-181c Induced hESC Differentiation by Targeting CARM1. [score:5]
An siRNA that specifically targets and inhibits miR-181c was synthesized by GenePharma (Shanghai, China). [score:5]
The expression of Nanog and the marker genes for specific differentiated lineages was restored in comparison to miR-181c -overexpressing cells (Figure 3D, 3E). [score:5]
The core pluripotency factors also recruit H3K27 methylases to the miR-181c promoter to inhibit its expression. [score:5]
Enforced Expression of miR-181c Suppresses CARM1 -mediated Nanog TranscriptionIn previous reports, histone H3 methylation on R17 has been identified as the main substrate of CARM1 in mouse ESCs. [score:5]
Suppression of miR-181c led to a comparable number of AP -positive colonies relative to wild-type cells (Figure 4C), and the expression of most of the marker genes for specific differentiated lineages was restored to wild-type levels (Figure 4D). [score:5]
Figure S4 Changes of pluripotency and cell morphology in response to overexpression of CARM1 and inhibition of miR-181c upon induction of hESC differentiation. [score:5]
0053146.g002 Figure 2The miR-181 family directly regulates CARM1 expression in hESC. [score:5]
To investigate whether CARM1 can be directly targeted by miR-181, we engineered luciferase reporters that have either the wild-type 3′UTR of CARM1, or a mutant 3′UTR with three point mutations in the target sites as a negative control (Fig. 2C). [score:5]
As reported in previous studies [35], the core pluripotency factors co-occupied the promoters of pri-miR-181c/d with Polycomb group proteins, which increased local H3 lysine 27 (H3K27) methylation and inhibited miR-181c expression. [score:5]
The miR-181 family directly regulates CARM1 expression in hESC. [score:5]
All the results indicated that CARM1 down-regulation may greatly contribute to the miR-181-meidated hESC differentiation. [score:4]
Future studies will explore how the expression of the miR-181 family is regulated in ESC differentiation and whether other transcriptional factors are associated with CARM1. [score:4]
Suppression of miR-181c Impedes hESC Differentiation through the CARM1-related Pathway. [score:3]
By contrast, the expression of mutant reporters was not repressed by miR-181 (Fig. 2D). [score:3]
Comparison of mature miR-181c expression was performed with an unpaired Student’s t test. [score:3]
ChIP analysis detected that CARM1 and histone H3R17 di-me were significantly enriched at the Nanog promoter in antago-miR-181c -overexpressing hESCs (Fig. S3B). [score:3]
Human ESCs were transfected with miR-181c inhibitor or NC RNA and then induced to differentiate by the addition of BMP4 in the absence of bFGF. [score:3]
Thus, we suggest that CARM1 is one of the key target genes of the miR-181 family during the progression of ESCs differentiation. [score:3]
The mature transcripts of the 4 members of the miR-181 family were all found to be significantly increased in differentiated hESCs, and miR-181c had the highest expression level (Fig. 2A). [score:3]
We also found that the expression levels of the miR-181c/d primary transcripts (pri-181c/d) were notably elevated after differentiation in comparison to the primary transcripts of miR-181a and miR-181b (pri-181a1/b1 and pri-181a2/b2) (Fig. 2B). [score:3]
Furthermore, CARM1 partly rescued the effects of miR-181c expression by elevating the transcript levels of Nanog and maintained hESCs colony morphology temporarily under differentiation conditions. [score:3]
Our work suggests that downstream targets of the miR-181 family include epigenetic factors that reconfigure the H3 arginine methylation signature during the process of hESC differentiation. [score:3]
By contrast, the suppression of miR-181c promotes the recruitment of endogenous CARM1 to the promoters of pluripotency genes, especially Nanog, to impede differentiation. [score:3]
Meanwhile, we found that CARM1 overexpression greatly rescued the effects of miR-181c on promoting ESC differentiation. [score:3]
Considering that the sites of the CARM1 3′UTR that are targeted by miR-181 family members are conserved in mammals, we suppose that the interaction between miR-181 and CARM1 is conserved in mESCs. [score:3]
To further reveal the mechanism of CARM1 -mediated gene regulation, we then assessed whether the CARM1 -mediated histone H3 methylation contributed to the regulation of pluripotency genes Oct4, Sox2 and Nanog after miR-181c transfection. [score:3]
miR-181 Family Members are Critical Regulators of CARM1 during hESC Differentiation. [score:2]
This blockade implicated miR-181c as a prominent regulator of differentiation. [score:2]
Our results also suggest that the miR-181/CARM1/core-pluripotency-factors regulatory loop may be a novel mo del pathway involved in the modulation of hESC pluripotency (Figure 4E). [score:2]
miR-181c leads to hESC differentiation through negative regulation of CARM1 and H3R17 methylation. [score:2]
We selectively transfected miR-181c mimics in undifferentiated hESCs to study the effect of miR-181 on hESCs differentiation. [score:1]
In our results from miR-181c -transfected hESCs, we also found that the global level of histone H3 methylation on R17 was also significantly decreased (Figure 3A). [score:1]
To study the role of endogenous miR-181 in repressing the CARM1 3′UTR reporter in differentiated hESCs, we co -transfected the wild-type 3′UTR luciferase reporter and the negative control luciferase into differentiated hESCs. [score:1]
This finding suggests that the miR-181 family may also promote differentiation by affecting histone modulation in mESCs. [score:1]
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4
[+] score: 252
We hypothesized that, in conjunction with the host pro-inflammatory response during early infection, miR-181 expression might be up-regulated in HeV-infected mammals, but perhaps the virus co-opts this up-regulation to support infection and viral spread in the host. [score:9]
Expression of miR-181 is up-regulated in circulating biofluids derived from in vivo mo dels of henipavirus diseasePrevious studies have reported that members of the miR-181 family are involved in different aspects of immune regulation [43– 45]. [score:9]
Importantly, levels of EphA5 and EphA7, but not EphA4, are reduced by overexpression of both miR-181a and miR-181d, indicating that these class A Ephs are target genes for the miR-181 family, and that the pro-fusion phenotype of miR-181 are, at least in part, due to its downregulation of specific class A Ephs. [score:8]
Expression of miR-181 is up-regulated in circulating biofluids derived from in vivo mo dels of henipavirus disease. [score:8]
As each miRNA can act as a suppressor of many target genes, we hypothesized that miR-181 and miR-17~93 families promoted henipavirus infection by suppressing multiple anti-viral host genes. [score:7]
This led us to hypothesize that miR-181 supported fusion by down -regulating the expression of one or more novel cellular factor(s) that antagonizes expression and/or activity of the henipavirus entry receptors, ephrin-B2 or–B3. [score:6]
miR-181 targets EphA5, EphA7 and EphB4, but not EphA4, for downregulation. [score:6]
Thus, a potential mo del for the pro-viral mechanism of miR-181 posits that the miRNA down-regulates expression of Ephs, increasing the pool of unbound ephrin-B2 or ephrin-B3 for henipavirus G glycoproteins to attach and trigger entry/membrane fusion. [score:6]
Intriguingly, even though the 3’UTR of EphB4 transcripts does not contain any sequence that is complementary to the seed region of miR-181, EphB4 levels were downregulated by miR-181 expression. [score:6]
These data show that endogenous levels of the henipavirus fusion regulators EphA5, A7 and B4 can all be significantly suppressed by miR-181 expression. [score:6]
We opted to assess all Ephs with putative miR-181 target sites as predicted by TargetScan [39, 40], namely EphA4, A5 and A7 (S4 Table). [score:5]
Verified miR-181 and miR-17~93 target genes predominantly inhibit henipavirus infection. [score:5]
Select Eph receptors inhibit HeV infection and cell-cell-fusion and are miR-181 target genes. [score:5]
Cross-referencing of results from the siRNA screen of host genes associated with HeV infection suggests that miR-181 and miR-17~93 target multiple host genes which are anti-viral for HeV, and that the net outcome of cellular expression of miR-181 or miR-17~93 is likely a host microenvironment that is more conducive for henipavirus infection. [score:5]
Since miR-181 specifically promotes infection of henipaviruses but not other paramyxoviruses, it is quite likely miR-181 increases membrane fusion by directly targeting viral and/or host molecules unique to the henipavirus fusion machinery. [score:4]
In fact, miR-181 downregulated ephrin-B3 and and HeV F glycoprotein by about 30 to 40%. [score:4]
Collectively, these observations demonstrate in two different in vivo mo dels that members of the miR-181 family are up-regulated early in the host during HeV infection, implicating a biological role for miR-181 in host immunity as well as in henipavirus pathogenesis. [score:4]
Consistent with this, we observed that miR-181 is up-regulated in sera of ferrets and blood of horses as early as day 1 during a henipavirus infection. [score:4]
We also sought to determine whether miR-181 preferentially regulates the expression of host proteins localized in a particular subcellular compartment. [score:4]
The screens, in addition to subsequent validation work, demonstrate a key role for miR-181 family members in regulating henipavirus syncytia formation and infection, and suggest several host miRNAs, including miR-17~93, as potential candidates for novel therapeutic targets. [score:4]
The mo del of miR-181 -mediated immune pathogenesis has potential implications for risk factors associated with susceptibility to henipavirus disease, as well as for the strategic design and development of novel immunotherapy for henipavirus infections. [score:4]
In contrast, EphA4 levels were not impacted by miR-181d, and were only modestly (11%) affected by miR-181a, demonstrating some level of specificity in the regulation of Eph receptor expression by miR-181. [score:4]
Accordingly, human EphB4 does contain a putative miR-181 binding site in its ORF, providing an avenue for miR-181 regulation of its expression. [score:4]
In stark contrast to henipaviruses, miR-181 has been shown to be inhibit infection of porcine reproductive and respiratory syndrome virus [63]. [score:3]
Collectively, these data suggest that the net outcome of miR-181 or miR17~93 expression is a cellular microenvironment that is more conducive for henipavirus infection. [score:3]
Expression of entry receptors ephrin-B2/B3 and viral fusion glycoproteins are not appreciably enhanced by miR-181. [score:3]
qRT-PCR analysis of miR-181 expression. [score:3]
Given the substantial impact of miR-181 on cell-cell fusion (Fig 5B and 5C), it was intriguing that the miRNA did not considerably enhance expression levels of host and viral molecules known to be involved in entry and fusion. [score:3]
Pie charts show the relative proportions of pro- and anti-viral target genes for miR-181 (C) and for miR-17~93 (D), with the number of genes printed. [score:3]
To this end, the list of experimentally-validated miR-181 targets (n = 78 genes) was obtained from miRTarBase was subjected to annotation enrichment analysis using the DAVID web service. [score:3]
Experimentally validated target genes for miR-181 and miR-17 families (miRTarBase, and their corresponding impact on HeV infection). [score:3]
Following qRT-PCR, miR-181 expression was analysed using the ΔΔC [T] method and normalised to U6. [score:3]
Impact of members of Eph receptor family on HeV infection [14] and their putative miR-181 binding sites (TargetScan). [score:3]
Members of the miR-181 and miR-17~93 families strongly promoted Hendra virus infection and appear to suppress multiple antiviral host molecules. [score:3]
Viral RNA synthesis is augmented by miR-181 over -expression. [score:3]
S4 TableImpact of members of Eph receptor family on HeV infection [14] and their putative miR-181 binding sites (TargetScan). [score:3]
That said, algorithmic analysis by TargetScan [39, 40] of all human Ephs does not predict miR-181 binding sites in the 3’ UTR of the mRNAs of EphB3 or EphB4 (S4 Table). [score:3]
Collectively, our data supports a mo del where simultaneous inhibition of multiple anti-fusion Ephs from both receptor classes by miR-181 contributes to greatly enhanced membrane fusion and infection. [score:3]
Additionally, miR-181 expression in human kidney tissues were found to be associated with increased transcription of genes of inflammation pathways [47]. [score:3]
It is tempting to speculate that the host pro-inflammatory response (of which blood miR-181 is correlated with) promotes the early phase of virus spread in the host, thereby contributing to disease progression and pathogenesis [43, 44, 46]. [score:3]
Dual miRNA screens reveal miR-181 and miR-17~93 families as promoters of henipavirus infection that target multiple anti-viral genes. [score:3]
corroborate what was observed by visual inspection, indicating that miR-181 overexpression induced a drastic 9- to 10-fold increase in fusion events relative to control (Fig 5C). [score:3]
This supports the mo del that miR-181 enhances syncytia formation by targeting Ephs that naturally associate with the henipavirus entry receptors ephrin-B2 and B3. [score:3]
A subset of class A Eph receptors contain putative miR-181 target sites. [score:3]
This analysis demonstrated an enrichment of miR-181 target genes associated with the nucleoplasm (p = 4.6e-5), while proteins associated with plasma membrane localization were not significantly enriched (p = 0.7). [score:3]
For instance, the ratio of anti-viral to pro-viral hits for validated miR-181 targets was 2.2 to 1 (Fig 2C). [score:3]
Values represent the sum of all the Z-scores, and demonstrate the predominance of anti-viral genes among the miR-181 and miR-17 targets. [score:3]
To test this hypothesis, we firstly mined the miRTarbase database [27] to identify all experimentally-validated target genes for miR-181 and miR17~93 families. [score:3]
Expression levels of miR-181 in biofluids of animals infected with HeV are increased. [score:3]
Infection promotion is primarily mediated via the ability of miR-181 to repress Eph receptors that negatively regulate henipavirus glycoprotein -mediated cell-cell fusion. [score:2]
To address whether miR-181 promotes entry of henipaviruses, a cell-cell fusion assay was performed using 293T effector cells expressing HeV F and G-glycoproteins [14]. [score:2]
Thus, we next investigated if miR-181 overexpression would enhance expression of the virus entry receptors ephrin-B2 and -B3, as well as the viral fusion glycoproteins F and G. miR-181a agonists were included in this analysis, subsequent to the validation of their pro-fusion nature in infection and fusion assays (S2 Fig). [score:2]
These results indicate that, in addition to its role in regulating fusion, miR-181 might act via other anti-viral host mediators to induce a situation that is broadly supportive of henipavirus replication. [score:2]
Previous studies have reported that members of the miR-181 family are involved in different aspects of immune regulation [43– 45]. [score:2]
Considering that EphB4 is most antagonistic towards fusion (Fig 7C), it likely makes the most significant contribution to the pro-fusion phenotype of miR-181. [score:1]
Similar to results observed in ferret, transient yet significant increases in circulating miR-181 molecules were observed during the early stages of infection. [score:1]
However, and rather intriguingly, unlike miR-181 (Fig 4), members of the miR-17~93 family appear to also exhibit pro-viral effects on a paramyxovirus from a different subfamily than the henipaviruses. [score:1]
The seed sequence of the miRNAs in this family (AAAGUG) is distinct from that of miR-181. [score:1]
Considering the striking pro-fusogenic activity of miR-181, we wondered whether this effect is unique to the miR-181 family of miRNAs. [score:1]
Thus, miR-181 promotes henipavirus infection at, or prior to, the step of viral RNA synthesis. [score:1]
To assess whether the pro-viral effects of miR-181 are specific to HeV, the in vitro activity of miR-181d agonists were tested on a range of viruses from different subfamilies of the Paramyxoviridae family. [score:1]
Interestingly, this infection enhancement seems to be primarily mediated via the ability of miR-181 to significantly augment henipavirus glycoprotein -mediated cell-cell fusion, implicating miR-181 in the enhancement of henipavirus entry. [score:1]
We found that miR-181 did not affect infection by paramyxoviruses from other genera, indicating specificity in the henipavirus-miR181 virus-host interaction. [score:1]
Congruent with this notion, viral RNA synthesis in a single round of infection is elevated in cells transfected with miR-181 agonists. [score:1]
miR-181 impacts henipavirus infection but not paramyxoviruses from other genera. [score:1]
In addition to miR-181, most members of the miR-17~93 family were pro-viral (Fig 2B). [score:1]
In order to narrow down the possible mechanisms by which miR-181 promotes henipavirus infection, we next sought to delineate the part of the virus life cycle at which miR-181 promotes infection. [score:1]
All four members of the miR-181 family exhibited consistent pro-viral phenotypes in both the agonist and antagonist screens (Figs 1D and 2A). [score:1]
miR-181 significantly enhances HeV F- and G -mediated cell-cell fusion. [score:1]
This pro-fusion effect is specific to the miR-181 family, as transfection with agonists of another strongly pro-viral miRNA (miR-17), did not appreciably alter syncytia formation. [score:1]
Even though it was not predicted to contain any miR-181 binding sites, EphB4 was the most anti-viral hit of the class B receptors in the RNAi screen and was previously shown to compete with HeV G glycoprotein for ephrin-B2 binding [38], so it was incorporated into our study as well. [score:1]
The scale of the pro-viral impacts of miR-181 members is especially remarkable if we compare their effects to that of miR-146a (Fig 2A), which we previously validated as pro-viral for HeV [22]. [score:1]
Since henipavirus mediated cell-cell fusion is both a surrogate mo del for virus entry as well as a natural phenomenon during late stages of infection, it is likely that in addition to enhancing henipavirus entry, miR-181 also promotes more efficient cell-to-cell spread of this virus by merging the cytosols of neighbouring cells more rapidly. [score:1]
Both complementary screens converged on members of four miRNA families (miR-181, miR-17~93, miR-520h, miR-548d) that strongly promoted henipavirus infection. [score:1]
Even though the role of miR-181 in inflammation and NKT-cell maturation has been documented [23, 43– 46], little has been reported about its role in the infection of other viruses. [score:1]
All four members of the miR-181 family significantly promoted HeV infection (Fig 2A). [score:1]
These results indicate that the enhancement effects of miR-181 are specific to the henipavirus genus. [score:1]
miR-181 significantly enhances HeV RNA synthesis and F- and G -mediated cell-cell fusion. [score:1]
Initial in silico analysis revealed that EphA4, EphA5 and EphA7 possess putative miR-181 binding sites in the 3’ UTRs of their transcripts. [score:1]
Cells were transfected with miR-181 agonists, and then infected with a high MOI (5) of HeV. [score:1]
To evaluate whether these anti-fusion Ephs are suppression targets of miR-181, the mRNA levels of the Ephs in agonist -transfected cells were measured by qRT-PCR. [score:1]
Interestingly, miR-181 -transfected cells induced substantially more, and larger, syncytia. [score:1]
We first looked at whether viral RNA synthesis was induced by miR-181 during a single round of HeV infection. [score:1]
This provides a coherent mechanistic mo del for how miR-181 may expedite host entry and virus spread during infection. [score:1]
Screen results suggested that miR-181d is one of the most pro-viral members of the family (Fig 2A, S1 Table and S2 Table), hence miR-181d was chosen as a representative member of the miR-181 family in the majority of subsequent experiments. [score:1]
In sum, these results indicate that HeV-glycoprotein mediated cell-cell fusion is greatly stimulated by miR-181, but not by miR-17, suggesting that miR-181 specifically facilitates henipavirus infection by enhancing host entry and, quite possibly, by supporting cell-to-cell spread during late stages of infection via syncytia formation. [score:1]
We show that miR-181 promoted infection of both wild-type HeV and NiV infections. [score:1]
Since all four members of the miR-181 family were pro-viral hits using this approach, we focused our validation efforts on miR-181. [score:1]
miR-181 promotes Hendra virus infection of human cells. [score:1]
1005974.g002 Fig 2(A and B) from miRNA screens for all miR-181 (A) and miR-17~93 (B) family members, represented by robust Z-scores. [score:1]
This study implicates miR-181 and certain class A Eph receptors as critical modulators of henipavirus membrane fusion, and highlights how the natural innate immune response of the host can be exploited by a RNA virus to promote cell-to-cell spread. [score:1]
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[+] score: 250
Other miRNAs from this paper: hsa-mir-93
Our cDNA array analysis demonstrated that FAS was the only miR-181c-target gene whose expression was uniformly upregulated in all five ES cell lines, whereas the expression of other candidate genes was different among the ES cells. [score:10]
Consistent with the data from in vitro experiments, xenograft ES mo dels also indicated that miR-181c repression is capable of inhibiting ES tumor development in vivo following restoration of FAS expression and translation. [score:8]
We show that miR-181c regulates FAS and the FAS -mediated apoptosis pathway by directly downregulating FAS expression. [score:8]
MiRNA, miR-181c, was significantly up-regulated, whereas FAS receptor expression was significantly down-regulated in all tested ES cells compared with hMSCs. [score:8]
Immunohistochemical studies revealed that the expression of FAS and cleaved caspase 3 in the xenografted tumors was inhibited by the transfection with anti-miR-181c and FAS expression vector (Fig.   6b). [score:7]
Thus, we can infer that the upregulation of FAS, resulting from transfection of anti-miR-181c or FAS expression vector, induced apoptosis of ES cells. [score:6]
Among 228 up-regulated miRNAs in five ES cells, the expression of miR-181c was increased by 2.85- to 5.57-fold in comparison with hMSCs. [score:6]
The level of FAS protein expression in the cells transfected with anti-miR-181c (20 nM) was up-regulated to 2.34-fold of that in the control cells (p < 0.01) (Fig.   2e). [score:6]
In the present study, miRNA array analysis showed that the expression of miR-181c was upregulated in all of the five tested ES cell lines. [score:6]
These results suggest that unregulated expression of miR-181c could contribute to ES by targeting FAS. [score:6]
Furthermore, the down-regulation of miR-181c in ES cells significantly suppressed tumor growth in vivo. [score:6]
Our results show that transfection with anti-miR-181c and FAS expression vector enhances caspase-8, and caspase 3/7 activity, and increases cleaved PARP expression levels. [score:5]
The number of cells positive for FAS expression was significantly increased in mice inoculated with anti-miR-181c (199 ± 21.8 cells/mm [2]) or FAS expression vector transfected cells (230.7 ± 45.7 cells/mm [2]) than that with untreated (65.6 ± 10.6 cells/mm [2]) or control-miR transfected cells (93.8 ± 16.8 cells/mm [2]) (p < 0.01). [score:5]
SK-ES-1 cells that were transfected with anti-miR-181c or FAS expression vector showed the increase in expression of FAS, and cleaved caspase 3, 7, and 8 (Fig.   5b). [score:5]
The BLAST and TargetScan analyses demonstrated a considerable complementarity in the sequence of miR-181c seed region with human FAS mRNA 3′un-translated region (3′-UTR) (Fig.   2a) suggesting the influence of miR-181c to FAS mRNA via association with 3′UTR of the mRNA. [score:5]
Analysis using several algorithms, such as BLAST and TargetScan, further suggested that FAS was a putative target of miR-181c. [score:5]
miR-181c-5p mimic, miR-181c-5p mutant, anti-miR-181c inhibitor, negative control miRNAs, FAS expression vector and Mock vector were transfected using Lipofectamine 2000. [score:5]
Although miR-181c might influence the expression of many genes, we focused on FAS as the target of miR-181c in ES cells. [score:5]
The results suggested that inhibition of expression of miR-181c also lead to reduction of in vivo growth of ES cells. [score:5]
Up-regulation of miR-181c is reported to be involved in tumor cell growth [4] and chemotherapy resistance [17] in other malignant tumors. [score:4]
Therefore, we analyzed the possibility that miR-181c might play an anti-cancer regulatory role in ES cells by targeting FAS. [score:4]
Our results are the first evidence that suggest that the same miR-181c mediated regulatory mechanism of FAS expression might exist in ES cells. [score:4]
FAS as a direct target of miR-181c in ES cells. [score:4]
Expression of miR-181c in ES cells. [score:3]
The number of cleaved caspase 3 expressing cells was significantly increased in mice inoculated with anti-miR-181c (170.9 ± 22.2 cells/mm [2]) or FAS vector (169.3 ± 37.4 cells/mm [2]) transfected cells than that with untreated (44.1 ± 3.6 cells/mm [2]) or control-miR transfected cells (49.7 ± 13.3 cells/mm [2]) (p < 0.01) (Fig.   6c). [score:3]
Forced expression of miR-181c resulted in the repression of FAS protein, indicating that miR-181c might function as an oncogene in ES cells. [score:3]
The results of the database analyses suggested that FAS was the strongest target of miR-181c. [score:3]
SK-ES-1 (1 × 10 [6] cells) were cultured and transfected with anti-miR-181c miRNA or FAS expression vector. [score:3]
Furthermore, the repression of miR-181c results in the inhibition of ES tumor growth in vivo. [score:3]
Growth inhibition of xenografted tumors by anti-miR-181c and FAS. [score:3]
The cell growth of SK-ES-1 (62.5 ± 14.9 × 10 [5] cells) was inhibited by the transfection of anti-miR-181c (80 nM) as determined by cell counting in comparison with negative control-miRNA transfected cells (93.1 ± 14.6 × 10 [5] cells) (p = 0.044) (Fig.   3a). [score:3]
Introducing anti-miR-181c into ES cell lines resulted in an increased expression of FAS2. [score:3]
Therefore, we hypothesized that an elevation in miR-181c results in inhibition of FAS mRNA expression, and we investigated our hypothesis. [score:3]
We hypothesized that the effect of FAS in ES cells might be mediated, at least in part, via miR-181c, directly or indirectly. [score:3]
Total of 20 mice were divided into four groups (5 mice each): (1) untreated control, (2) transfected with control-miRNA, (3) transfected with anti-miR-181c, and (4) transfected with FAS expression vector. [score:3]
The results suggested that the stability of FAS mRNA was inhibited by miR-181c in ES cell lines. [score:3]
Effects of anti-miR-181c on the expression of FAS. [score:3]
Fig.  6Suppression of ES tumor growth by anti-miR-181c and FAS vector in vivo. [score:3]
In this experiment, de novo mRNA transcription was blocked using actinomycin D (10 μg/ml), an inhibitor of mRNA transcription, since we attempted to determine whether FAS mRNA stability would be affected by miR-181c. [score:3]
The treatment with anti-miR-181c also inhibited the proliferation of RD-ES cells (88.5 ± 13.6 × 10 [5] cells) in comparison with that of NC-miRNA transfected cells (125.2 ± 14.2 × 10 [5] cells) (p < 0.01) (Fig.   3b). [score:3]
The results showed that the expression of miR-181c was increased in all five ES cell lines, whereas that of FAS was repressed in all five ES cell lines. [score:3]
a Cells were untreated or transfected with negative control miR, anti-miR-181c or FAS expression vector and stained with propidium iodine and analyzed for cell cycle distribution. [score:3]
a Four groups of mice inoculated with (1) untreated SKES1 cells (n = 7); (2) transfected with negative control-miR (n = 7); (3) transfected with anti-miR-181c (n = 7); and (4) transfected with FAS expression vector (n = 7) were generated. [score:3]
a, b Anti-miR-181c inhibits cell growth in SKES1 cells, and RDES cells. [score:3]
Reduction of miR181c increased expression of FAS. [score:3]
The microRNAs, miR-181c-5p mimic (5′-AACAUUCAACCUGUCGGUGAGU-3′), miR-181c-5p mutant (5′-AUGUAAGUACCUGUCGGUGAGU-3′), hsa-miR-181c inhibitor or negative control (NC) miRNAs were purchased from Invitrogen. [score:3]
Transfection of anti-miR-181c or FAS expression vector into SKES1 cells resulted in the increase of sub G1 fraction but did not influence the proportion between G1/G0, S and G2/M phases. [score:3]
Therefore, we examined the effects of miR-181c on the expression of FAS in ES cells by the transfection of miR-181c and a mutated miR-181c into SK-ES-1 cells. [score:3]
We examined the functions of miR-181c in the regulation of its possible target gene, FAS, and the changes in the biological characteristics of ES cell lines. [score:2]
Treatment with anti-miR-181c (40 nM) also inhibited the proliferation of SK-ES-1 cells (72.1 ± 22.5 × 10 [5] cells) compared to in negative control-miRNA -transfected cells (112.7 ± 17.5 × 10 [5] cells) (p = 0.031). [score:2]
FAS expression in SK-ES-1 cells was increased transfected with the anti-miR-181c (288 ± 2.9%) and FAS vector (303 ± 3.1%) compared to in control cells (100%). [score:2]
p < 0.05 was considered to indicate significance: *p < 0.05, **p < 0.01 The effects of miR-181c inhibitor on the growth of xenografts in vivo were examined next. [score:2]
Several studies have shown that miR-181c is involved in various biological and pathological processes, including development, differentiation, inflammation, apoptosis, and cancer [5, 16]. [score:2]
When SK-ES-1 cells were transfected with the anti-miR-181c, the expression of cleaved PARP (342 ± 14.1%), cleaved caspase 3 (372 ± 12.2%), cleaved caspase 7 (321 ± 5.95%) and cleaved caspase 8 (315 ± 3.24%) was dramatically increased compared to in untreated SE-ES-1 cells (100%). [score:2]
These results suggest that miR-181c is a regulator of FAS mediated apoptosis in Ewing’s sarcoma. [score:2]
Therefore, miR-181c may have affected FAS mRNA directly at least in part. [score:2]
We observed an increased intracellular miR-181c level by 5.01 ± 0.94 folds compared with control-miR (Fig.   2b) and significantly decreased FAS expression by 0.43 ± 0.23 folds at mRNA level after the transfection with miR-181c oligonucleotide (Fig.   2c). [score:2]
Since the introduction of anti-miR-181c lead to the increase in the expression of FAS, we also investigated the effects of anti-miR-181c on the growth of ES cells. [score:1]
The aim of our study is to evaluate whether the expression of FAS is repressed by miR-181c and the pathway could play a role in malignancy in ES cells. [score:1]
In anti-miR-181c transfected cells, the levels of FAS protein remarkably elevated in comparison with untreated or control oligonucleotide -treated cells (Fig.   2d). [score:1]
The present study indicates the inverse correlation of miR-181c and FAS in ES cells for the first time. [score:1]
Ewing’s sarcoma MicroRNA miR-181c FAS Ewing’s sarcoma (ES) is the second most frequent primary malignant bone tumor in children and adolescents. [score:1]
Although the data demonstrated in the present study needs to be confirmed using clinical samples of ES, the novel information regarding the link between miR-181c and FAS in ES cells would be beneficial for the better understanding of oncogenesis of ES and provide novel strategies for clinical application in the future. [score:1]
Also, when we examined whether microRNA that binds to the FAS mRNA 3′-UTR is elevated in a microRNA array, we found that miR-181c was elevated in all five Ewing sarcoma cell lines. [score:1]
b, c After actinomycin D administration, the miR-181c and mRNA expression level in the negative control-miR, miR-181c, and miR-181c mutant was evaluated by qRT-PCR. [score:1]
a Possible binding sites of miR-181c at the 3′UTR of FAS mRNA. [score:1]
Additionally, anti-miR-181c prohibited cell growth and cell cycle progression in ES cells. [score:1]
a FAS and apoptosis related factors to study the effect of anti-miR-181c and FAS vector on FAS related apoptotic pathway in SKES1 cells. [score:1]
The miR-181c transfected cells increased 5.01 times, which is the combined total of endogenous miR-181c and transfected oligo, but we have not analyzed the exact proportion of endogenous miR-181c. [score:1]
SK-ES-1 cells (2 × 10 [6]) transfected with anti-miR-181c were suspended in 100 μl normal saline and injected into the gluteal region of BALB/c nu/nu mouse. [score:1]
Furthermore, sequence analysis suggested possible association of miR-181c with 3′UTR of FAS. [score:1]
Our data shows that miR-181c promotes the proliferation of ES cells via induction of anti-apoptosis mechanisms, and not by affecting the cell cycle pausing at G1/G0 phase. [score:1]
The introduction of anti-miR-181c into SKES1 cells resulted in the decreased growth of subcutaneous xenografted tumors in nude mice (Fig.   6a). [score:1]
Each sequence of miR-181c (Wt) and its mutant (Mut). [score:1]
However, there was no difference in the proportion of the G0/G1, S, G2/M divisions among the 4 groups, so transfection of the anti-miR-181c and FAS vector had no effect on the cell cycle. [score:1]
Anti-miR-181c also promoted apoptosis in ES cells. [score:1]
FACS analysis revealed that the number of SK-ES-1 cells transfected with anti-miR-181c (6.2 ± 1.2%) or FAS vector (7.7 ± 1.1%) in sub-G1 phase was significantly higher than that in untreated (0.5 ± 0.4%) and negative control (0.8 ± 0.2%) transfected cells. [score:1]
The size of tumors in mice inoculated with anti-miR-181c -transfected SK-ES-1 cells (466.5 ± 28.1 cells/mm [3]) or FAS vector -transfected cells (385.5 ± 16.9 cells/mm [3]) was significantly smaller than that with untreated (1165.8 ± 74.1 cells/mm [3]) and NC-miRNA -transfected cells (1021.2 ± 54.7 cells/mm [3]). [score:1]
This result is regarded as verification to confirm that miR-181c oligonucleotides can be properly transfected into the cell. [score:1]
Apoptosis induction by anti-miR-181c and FAS. [score:1]
The results indicated that anti-miR-181c and FAS might have no effect on the cell cycle progression of ES cells. [score:1]
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Collectively, all data from our study demonstrate that miR-181c over -expression alleviated lung injury in COPD, as evident from the resulting amelioration of lung injury, reduction of the inflammatory response, neutrophil infiltration, and ROS generation, and down-regulation of CCN1 expression. [score:8]
These results suggest the critical roles of miR-181c and its target CCN1 in COPD development, and provide potential therapeutic targets for COPD treatment. [score:6]
Taken together, our data suggest the critical roles of miR-181c and its target CCN1 in COPD development, and provide potential therapeutic targets for COPD treatment. [score:6]
In the present study, we found that miR-181c over -expression alleviated lung injury in COPD, and decreased the inflammatory response, neutrophil infiltration, and ROS generation, whereas miR-181c inhibition showed the opposite effect on COPD development. [score:6]
Functional assays demonstrated that miR-181c over -expression decreased the inflammatory response, neutrophil infiltration, reactive oxygen species (ROS) generation, and inflammatory cytokines induced by CS, while its down-regulation produced the opposite effects. [score:5]
Yang et al. recently reported that miR-181c limits nitration stress of endothelial cells in diabetic db/db mice through inhibiting the expression of FoxO1 [25]. [score:5]
Moreover, levels of IL-6 and IL-8 in lung tissues were increased in CS-exposed mice; miR-181c over -expression reduced levels of IL-6 and IL-8, demonstrating that miR-181c can suppress the inflammatory response in COPD. [score:5]
CCN1 expression was increased in lung tissues of COPD patients, and was negatively correlated with miR-181c expression in human COPD samples (p < 0.01). [score:5]
miR-181c was over-expressed or inhibited using specific agomiRs and antagomiRs, respectively, which were synthesized by RiboBio Co. [score:5]
The relationship between miR-181c expression and CCN1 mRNA expression levels was analyzed using Pearson correlation analysis. [score:5]
Over -expression of miR-181c impeded CS -induced lung injury, while inhibition of miR-181c enhanced lung injury. [score:5]
Over -expression of miR-181c alleviated lung injury and neutrophil infiltration in CS-exposed mice, whereas miR-181c inhibition had the opposite effect. [score:5]
In the present study, CCN1 was found to be the direct and functional target of miR-181c. [score:4]
We also observed a down-regulation of miR-181c in HBECs and a mouse mo del after cigarette smoke (CS) exposure. [score:4]
Wang and colleagues reported that miR-181c targets Bcl-2 and regulates mitochondrial morphology in myocardial cells [24]. [score:4]
Functional assays demonstrated that miR-181c over -expression alleviated and miR-181c inhibition aggravated lung injury in COPD. [score:4]
miR-181c exerts its effect via negatively regulating CCN1 expression in COPD. [score:4]
A sequence with a mutation in the miR-181c target site (MUT) was synthesized. [score:4]
Taken together, these findings demonstrated that miR-181c may exert its effect through regulating CCN1 expression in COPD. [score:4]
In addition, CCN1 was identified as the direct target of miR-181c in COPD. [score:4]
To verify that CCN1 is a direct target of miR-181c, we cloned a reporter plasmid containing the wild-type (WT) or mutant (MUT) 3′-UTR of CCN1. [score:4]
BALF fluid COPD Chronic obstructive pulmonary disease CS Cigarette smoke CSE Cigarette smoke extract HBECs Human bronchial epithelial cells miR-181c microRNA-181c qRT-PCR Quantitative real-time PCR ROS Reactive oxygen species This work was supported by the grants from the Shanghai Municipal Health and Family Planning Commission scientific research project (201540123), and Key Department of Shanghai Fifth People’s Hospital (2017WYZDZK07). [score:3]
The expression levels of miR-181c and CCN1 were detected using SYBR Premix Ex Taq (TaKaRa) according to the manufacturer’s instructions. [score:3]
The cells were harvested for RNA isolation and miR-181c expression was analyzed. [score:3]
These data indicated that miR-181c was decreased in COPD and may serve as an inhibitor of COPD. [score:3]
Fang and colleagues showed that miR-181c targeting TRIM2 ameliorates cognitive impairment induced by chronic cerebral hypoperfusion in rats [23]. [score:3]
Previous studies have shown that miR-181c is implicated in regulation of the inflammatory response, energy metabolism, and cancer development. [score:3]
When miR-181c was inhibited, ROS generation increased significantly, clearly indicating an important role of miR-181c in ROS generation during COPD. [score:3]
We showed that miR-181c was significantly down-regulated in lung tissues from patients with COPD compared to individuals who had never smoked (p < 0.01). [score:3]
miR-181c has also been shown to be down-regulated in patients with COPD compared to never smokers [8]. [score:3]
Data represent mean ± SD from three independent experiments; * p < 0.05, ** p < 0.01 We first determined the expression pattern of miR-181c in a total of 34 human lung tissue samples, including 8 never smokers, 8 smokers without COPD and 18 COPD patients. [score:3]
In addition, ROS generation was markedly increased in CS-exposed mice, and miR-181c over -expression reduced ROS generation, indicating that miR-181c decreased ROS generation in COPD. [score:3]
h Pearson correlation analyses between miR-181c levels and mRNA expression levels of CCN1 in human COPD tissues. [score:3]
Levels of miR-181c and mRNAs were normalized to RNU6B small nuclear RNA and β-actin, respectively, to yield a 2 [-ΔΔCT] value for relative expression of each transcript. [score:3]
c miR-181c expression was tested in lungs of mice exposed to air or CS for 4 or 24 weeks. [score:3]
a The relative expression levels of miR-181c were examined by qRT-PCR in lung tissues of 8 never smokers, 8 smokers without COPD and 18 COPD patients. [score:3]
Levels of miR-181c expression in lung tissues of COPD patients and CS-exposed mice. [score:3]
We also analyzed the miR-181c expression in a mouse mo del of CS exposure. [score:3]
Consistent with our observations in the human lung, miR-181c was significantly down-regulated in lung tissues of mice exposed to CS for 24 weeks, compared with air-exposed mice (p < 0.05; Fig. 1c). [score:3]
miR-181c expression was detected in human lung tissue samples of 34 patients, an in vivo murine mo del of CS exposure, and primary human bronchial epithelial cells (HBECs) by qRT-PCR. [score:3]
These results indicated that miR-181c inhibited the inflammatory response in CS-exposed cells and mice. [score:3]
Here, we showed that the expression of miR-181c was decreased significantly in COPD clinical samples. [score:3]
miR-181c COPD CCN1 Lung injury Inflammatory cytokines Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and a progressive airflow limitation due to airway and/or alveolar abnormalities usually caused by an abnormal inflammatory response of the lung to noxious particles and gases [1]. [score:3]
We first determined the expression pattern of miR-181c in a total of 34 human lung tissue samples, including 8 never smokers, 8 smokers without COPD and 18 COPD patients. [score:3]
b The expression levels of miR-181c in HBECs 24 h after CSE exposure. [score:3]
In addition, correlation analyses revealed that miR-181c levels were negatively correlated with expression levels of CCN1 in human COPD tissues (Fig. 4h). [score:3]
Moreover, miR-181c levels were negatively correlated with expression levels of CCN1 in human COPD samples. [score:3]
Subsequent investigation found that CCN1 was a direct target of miR-181c. [score:2]
Subsequent investigation revealed that CCN1 is the direct and functional target of miR-181c in COPD. [score:2]
miR-181c is a member of the miR-181 family and plays an important role in inflammatory response, energy metabolism, and cancer development [11]. [score:2]
Compared with never smokers, the relative expression levels of miR-181c were significantly decreased in lung tissues of smokers and COPD patients (p < 0.01; Fig. 1a). [score:2]
Mutations in the complementary site for the seed region of miR-181c in 3′-UTR of CCN1 gene are indicated. [score:2]
In addition, we exposed HBECs to 2.5% CSE or control medium, and found that the expression of miR-181c in CSE -treated cells was significantly decreased by 53% as compared with control cells (p < 0.01; Fig. 1b). [score:2]
a miR-181c binding sites in the CCN1 3′-UTR. [score:1]
Effect of miR-181c on inflammatory cytokine levels in CS-exposed mice and cells. [score:1]
However, the role of miR-181c in COPD remains unclear. [score:1]
Co-transfection of agomiR-181c and CCN1–3′-UTR-WT strongly decreased luciferase activity, whereas co-transfection of agomiR-181c and CCN1–3′-UTR-MUT did not alter luciferase activity (Fig. 4b), indicating that miR-181c can bind to the CCN1–3′-UTR. [score:1]
In our study, we explored the biological activity of miR-181c in COPD. [score:1]
CCN1, also named Cyr61, was predicted to harbor one highly conservative miR-181c binding site in the 3′-UTR of CCN1 at position 519–525 (Fig. 4a). [score:1]
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c-d CTDSPL expression was significantly inhibited after transfection with si-CTDSPL-1 and si-CTDSPL-2 in MUM2b and OCM1a cells, whereas pRB and E2F1 expression was significantly increased in MUM2b and OCM1a cells after transfection with si-CTDSPL-1 and si-CTDSPL-2. The gray level was analyzed by histogram seperately (*P < 0.05) miR-181 contributes to cell cycle progression via its target CTDSPL, which in turn increases expression of the cell cycle effector pRB/E2F1 in UM cellsOur work found that miR-181b is overexpressed in melanoma tissues and most UM cells and promotes cell cycle progression by repressing CTDSPL expression in UM cells. [score:15]
Although miR- 181c and - 181d mimics and inhibitors could promote and inhibit CTDSPL expression through the same binding site in the CTDSPL gene, miR-181c and miR- 181d were not upregulated in most UM cells except for a slight increase in miR-181c in OCM1 cells and miR-181d in OCM1a cells. [score:10]
In contrast, the fraction of cells in G0/G1 phase was significantly increased by 12-15%, and the period of S-phases was significantly decreased 8-12% after the inhibitors of miR- 181 family members were transfected into OCM1a cells Bioinformatics and molecular biology assays confirmed CTDSPL as a target of miR-181 family membersTo identify the target gene(s) of miR-181, candidate genes were identified using the miRNA target prediction database TargetScan [13] (http://www. [score:10]
The expression levels of miR-181c and miR-181d were not upregulated in most UM cell lines, except for a slight increase in miR-181c in OCM1 cells and a mild upregulation of miR-181d in OCM1a, both less than 10-fold. [score:9]
In contrast, the fraction of cells in G0/G1 phase was significantly increased by 12-15%, and the period of S-phases was significantly decreased 8-12% after the inhibitors of miR- 181 family members were transfected into OCM1a cells To identify the target gene(s) of miR-181, candidate genes were identified using the miRNA target prediction database TargetScan [13] (http://www. [score:9]
d and (f) Overexpression or knockdown of miR-181 expression inhibited or enhanced the Renilla luciferase activity, respectively. [score:8]
e and (g) The Renilla luciferase activity was nearly unchanged after mimics and inhibitors of miR- 181 family members were transfected with the mutated 3’-UTR of CTDSPL miR-181b was extremely overexpressed in melanoma tissues and most UM cellsTo investigate the expression profile of miR-181 family members in UM, microarray technology was used to detect the expression of miR-181 family members in melanoma tissues. [score:7]
miR-181a expression was also upregulated, while miR-181c and miR-181d were essentially unchanged (Fig.   3a). [score:6]
Western blot assays further indicated that mimics of miR-181 family members led to the reduced expression of CTDSPL, while inhibitors led to the increased expression of CTDSPL in MUM2b cells (Fig. 2b-c, P < 0.05). [score:6]
The expression levels of miR-181c and miR- 181d were not upregulated in most UM cell lines, except for a slight increase in miR- 181c in OCM1 cells and miR- 181d in OCM1a cells, both less than 10-fold. [score:6]
These data provide strong evidence that the miR-181 family members inhibit CTDSPL gene expression by directly binding to sites within its 3’-UTR. [score:6]
miR-181 contributes to cell cycle progression via its target CTDSPL, which in turn increases expression of the cell cycle effector pRB/E2F1 in UM cells. [score:5]
To examine whether miR-181 family members could directly regulate CTDSPL expression, 293 T cells were transfected with a luciferase reporter construct containing the putative wild-type and mutant 3’-UTR of CTDSPL binding sites, together with one of the following miRNAs: miR-181a, -181b, -181c, -181d, miR-NC, as-miR-181a, - 181b, - 181c, or - 181d. [score:5]
e and (g) The Renilla luciferase activity was nearly unchanged after mimics and inhibitors of miR- 181 family members were transfected with the mutated 3’-UTR of CTDSPL To investigate the expression profile of miR-181 family members in UM, microarray technology was used to detect the expression of miR-181 family members in melanoma tissues. [score:5]
miR-181 family members are highly conserved, and their upregulation promotes cell cycle progression. [score:4]
Thus, miR-181 induces cell cycle progression by repressing the downstream target CTDSPL, which in turn results in the phosphorylation of RB and an accumulation of the downstream cell cycle effector E2F1 Recently, miRNAs have emerged as important cellular regulators that mediate cellular proliferation and progression. [score:4]
Fig. 2CTDSPL is a direct target of miR-181 family members. [score:4]
The results demonstrated that mimics of miR-181 family members promoted cell cycle progression, while inhibitors of miR-181 family members led to cell cycle arrest (Fig. 1b-e). [score:3]
There are five predicted target sites in the 3’-UTR of CTDSPL sequence for miR-181 family members. [score:3]
MiR-181 family members were found to be highly homologous across different species and their upregulation significantly induces UM cell cycle progression. [score:3]
miR-181 overexpression in UM cells induces progression through the G1/S transition and promotes S-phase entry. [score:3]
miR-181 family members were predicted to target CTDSPL, which had previously been denoted as RBSP3 (RB1 serine phosphatase from human chromosome 3), a key downstream mediator of cell cycle progression, and has been reported to participate in acute myeloid leukemia pathogenesis [6]. [score:3]
To determine the common target region of the miR-181 family in CTDSPL, a segment of wild-type and mutated 3’-UTR of the human CTDSPL cDNA was constructed. [score:3]
miR-181 family members were found to be highly homologous and have the same target, CTDSPL. [score:3]
However, the expression and function of the miR-181 family members in the pathogenesis of UM had not been established. [score:3]
Fig. 6 miR-181 targets CTDSPL, which modulates the cell cycle effector E2F1. [score:3]
These findings constitute a comprehensive foundation for future research on the important role miR-181 in the developmental pathology of UM. [score:2]
These results highlight that miR-181 family members, especially miR-181b, may be useful in the development of miRNA -based therapies and may serve as novel diagnostic and therapeutic candidate for UM. [score:2]
miR-181 family members are highly conserved, and their upregulation promotes cell cycle progressionTo explore the relationship among miR-181 family members, their sequence homology was investigated. [score:2]
Bioinformatics and molecular biology assays confirmed CTDSPL as a target of miR-181 family members. [score:2]
The expression level of miR-181 family in human uveal melanoma cell lines was measured via real-time PCR (RT-PCR). [score:1]
miR-181a and miR-181b are transcribed from two separated gene loci (miR-181a-1/miR-181b-1 and miR-181a-2/miR-181b-2), while miR-181c and miR-181d are transcribed from another locus [6]. [score:1]
miR-181 Uveal melanoma CTDSPL E2F1 Cell cycle Recently, miRNAs were found to play critical roles in many different cellular processes, especially in tumor progression. [score:1]
Thus, miR-181 induces cell cycle progression by repressing the downstream target CTDSPL, which in turn results in the phosphorylation of RB and an accumulation of the downstream cell cycle effector E2F1 To explore the relationship among miR-181 family members, their sequence homology was investigated. [score:1]
Next, miR-181 family members were detected in various types of UM cells, including OCM1, SP6.5, VUP, OCM1a, MUM2b and 92-1 cells. [score:1]
MiR-181 family members are key negative regulators of CTDSPL -mediated cell cycle progression. [score:1]
Evolutionary conservation analysis of the miR-181 family members indicated that the sequences of miR-181a, -181b, -181c, and -181d are partly conserved in Homo sapiens, Mus musculus, Rattus norvegicus, Bos taurus and Pan troglodytes (Fig.   1a). [score:1]
The hollow white rectangle indicates the five different gene loci of the miR-181 family members. [score:1]
Schematic representation of the pathway modulated by miR-181 in UM cells progressing through the cell cycle. [score:1]
To investigate the potential roles of miR-181 family members, miR-181 family mimics (miR-181a, -181b, -181c, and -181d) or inhibitors (as- miR-181a, -181b, -181c, and -181d) were separately transfected into MUM2b and OCM1a cells. [score:1]
MUM2b (3 × 10 [5]) or OCM1a (5 × 10 [5]) cells were cultured overnight in 6-well plates and transfected with 200 nM miR-NC, miR-181 family mimics, or as- miR-181 family members (GenePharma Co. [score:1]
The predicted sequences to which miR-181 binds in the 3’-UTR of CTDSPL are conserved in humans (Fig.   2a). [score:1]
Fig. 1The conservation and cell cycle analysis of miR-181 family members. [score:1]
The miR-181 family contains four miRNAs (miR-181a/b/c/d). [score:1]
miR-181a, - 181b, -181c and -181d are miR-181 members of the family, which has been rarely studied, especially uveal melanoma. [score:1]
However, the homology among the miR-181 family members and the contribution of miR-181a, -181b, -181c and -181d in UM have not yet been clarified. [score:1]
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The results showed that miR-181 overexpression significantly decreased the luciferase activity, and mutations in the miR-181 binding site from the DAX-1 3′-UTR abolished this effect, suggesting that miR-181 directly inhibited DAX-1 expression by targeting the 3′-UTR (Fig. 4B). [score:11]
miR-181 targets the DAX-1 3′-untranslated region (3′-UTR) and downregulates its expression. [score:10]
They demonstrate that miR-181 overexpression causes the upregulation of AR target genes, suggesting that the proliferative role of miR-181, at least in part, may be dependent on androgen signaling. [score:8]
In the present study, elevated expression levels of AR target genes and proteins, including prostate-specific antigen, cyclin -dependent kinase (CDK) 1 and CDK2, was observed in LNCaP cells overexpressing miR-181 (Fig. 5). [score:7]
Therefore, these results suggest that miR-181 may negatively regulate DAX-1 expression at the translational level in LNCaP cells. [score:6]
In order to understand the underlying mechanism, potential targets of miR-181 were determined using TargetScan software. [score:5]
Previous studies have demonstrated that the upregulation of hepatic miR-181 promotes the growth, clonogenic survival, migration and invasion of hepatocellular carcinoma cells (7, 8). [score:4]
It was found that miR-181 is significantly upregulated in cancer tissues compared with that in normal adjacent tissues, as shown in Fig. 1. Since miR-181 was found to be upregulated in prostate cancer tissues, the effect of miR-181 on prostate cancer cell growth was investigated. [score:4]
Furthermore, in the present study DAX-1 was identified as a direct target of miR-181 in prostate cancer cells. [score:4]
miR-181 is upregulated in prostate cancer tissues. [score:4]
In addition, miR-181 overexpression was observed to promote the growth of LNCaP tumors in nude mice. [score:3]
The results suggest that miR-181 may be a potential therapeutic target for the treatment of prostate cancer in the future. [score:3]
The expression of miR-181 was analyzed in prostate cancer tissues and adjacent normal tissues using qPCR. [score:3]
DAX-1 was identified as a potential target of miR-181. [score:3]
In addition, the average tumor weight was significantly increased by miR-181 overexpression (Fig. 3C), suggesting that miR-181 may promote tumor growth in vivo. [score:3]
Furthermore, miR-181 overexpression decreased the percentage of cells in the G1 phase and increased the percentage of cells in the S phase (Fig. 2D). [score:3]
miR-181 overexpression promotes prostate cancer cell proliferation in vitro. [score:3]
Furthermore, the expression level of miR-181 is significantly associated with overall survival in hematological malignancies and may be an important clinical prognostic factor for patients with hepatocellular carcinoma (9). [score:3]
Therefore, in the present study, the expression of miR-181 was determined in prostate cancer tissues. [score:3]
A total of 2×10 [5] LNCaP cells stably expressing miR-181 or NC were injected subcutaneously into the dorsal flank of the mice. [score:3]
In the present study, it was demonstrated for the first time, to the best of our knowledge, that miR-181 overexpression may promote cell proliferation and cell-cycle progression in LNCaP cells. [score:3]
In combination, these results further confirm that DAX-1 is an important target gene of miR-181 in prostate cancer cells. [score:3]
Mutations were introduced in potential miR-181 binding sites using a site-directed mutagenesis kit (Qiagen). [score:3]
miR-181 overexpression promotes tumor growth in vivo. [score:3]
Therefore, miR-181 may be an onco-miRNA in the development of prostate cancer. [score:2]
To analyze miR-181 expression, specific stem-loop reverse transcription primers (Invitrogen Life Technologies) were used. [score:2]
The tumor size and volume were markedly increased in mice injected with LNCaP cells overexpressing miR-181 compared with those in control mice (Fig. 3A and B). [score:2]
To investigate whether DAX-1 may be directly targeted by miR-181, a luciferase reporter vector was constructed, containing the putative miR-181 binding sites within the DAX-1 3′-UTR. [score:2]
To further investigate the function of miR-181 on tumor growth in vivo, LNCaP cells with stable overexpression of miR-181 were generated and injected subcutaneously into the dorsal flank of nude mice. [score:1]
Notably, the 3′-UTR of DAX-1 mRNA was observed to contain a complementary site for the seed region of miR-181 (Fig. 4A). [score:1]
Furthermore, miR-181 mimics decreased the endogenous protein levels of DAX-1, as indicated by western blot analysis (Fig. 4C), while the DAX-1 mRNA levels remained unchanged (Fig. 4D). [score:1]
LNCaP cells were transfected with miR-181 mimics or NC (Fig. 2A). [score:1]
In conclusion, the present study provides a novel role for miR-181 in prostate cancer cell proliferation. [score:1]
Furthermore, the targets of miR-181 were investigated in order to determine the underlying mechanism of miR-181 in prostate cancer. [score:1]
Human miR-181 mimics and negative controls (NC) were purchased from Qiagen (Shanghai, China). [score:1]
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9
[+] score: 92
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7e, hsa-mir-20a, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-31, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-204, hsa-mir-212, hsa-mir-181a-1, hsa-mir-221, hsa-mir-23b, hsa-mir-27b, hsa-mir-128-1, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-143, hsa-mir-200c, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-200a, hsa-mir-30e, hsa-mir-148b, hsa-mir-338, hsa-mir-133b, dre-mir-7b, dre-mir-7a-1, dre-mir-7a-2, dre-mir-10b-1, dre-mir-181b-1, dre-mir-181b-2, dre-mir-199-1, dre-mir-199-2, dre-mir-199-3, dre-mir-203a, dre-mir-204-1, dre-mir-181a-1, dre-mir-221, dre-mir-222a, 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-7e, dre-mir-7a-3, dre-mir-10b-2, dre-mir-20a, dre-mir-21-1, dre-mir-21-2, dre-mir-23a-1, dre-mir-23a-2, dre-mir-23a-3, dre-mir-23b, dre-mir-24-4, dre-mir-24-2, dre-mir-24-3, dre-mir-24-1, dre-mir-26b, dre-mir-27a, dre-mir-27b, dre-mir-29b-1, dre-mir-29b-2, dre-mir-29a, dre-mir-30e-2, dre-mir-101b, dre-mir-103, dre-mir-128-1, dre-mir-128-2, dre-mir-132-1, dre-mir-132-2, dre-mir-133a-2, dre-mir-133a-1, dre-mir-133b, dre-mir-133c, dre-mir-143, dre-mir-148, dre-mir-181c, dre-mir-200a, dre-mir-200c, dre-mir-203b, dre-mir-204-2, dre-mir-338-1, dre-mir-338-2, dre-mir-454b, hsa-mir-181d, dre-mir-212, dre-mir-181a-2, hsa-mir-551a, hsa-mir-551b, dre-mir-31, dre-mir-722, dre-mir-724, dre-mir-725, dre-mir-735, dre-mir-740, hsa-mir-103b-1, hsa-mir-103b-2, dre-mir-2184, hsa-mir-203b, dre-mir-7146, dre-mir-181a-4, dre-mir-181a-3, dre-mir-181a-5, dre-mir-181b-3, dre-mir-181d, dre-mir-204-3, dre-mir-24b, dre-mir-7133, dre-mir-128-3, dre-mir-7132, dre-mir-338-3
Upregulation of miR-21, miR-31 and miR-181c leads to the downregulation of inhibitors and suppressors such as pdcd4, tgfbr2, bcl2l13, rgs5 and chka, downregulated genes with anti-proliferative functions. [score:14]
Fig 7 summarizes the gene regulatory circuit for miR-21, miR-31 and miR-181c, the 3 validated, shared upregulated miRNAs, with downregulated putative target genes that have functional relationships with conserved blastema -associated genes. [score:10]
Following injury, three miRNAs (miR-21, miR-31 and miR-181c) are commonly upregulated and target a set of five commonly downregulated genes shown with blue lines. [score:9]
0157106.g007 Fig 7Following injury, three miRNAs (miR-21, miR-31 and miR-181c) are commonly upregulated and target a set of five commonly downregulated genes shown with blue lines. [score:9]
These filtering criteria identified 136 downregulated genes with predicted binding sites in the 3’-UTRs for any of the 5 common upregulated miRNAs (miR-21, miR-31, miR-181b, miR-181c and miR-7b) (S21 Table). [score:7]
These studies confirmed miR-21, miR-181c and miR-31 were consistently upregulated in all three organisms and miR-181b and miR-7b were upregulated in both zebrafish and bichir (Fig 3). [score:7]
S22 Table Zebrafish Ensembl gene identifiers for 58 genes downregulated in three mo dels with predicted miRNA binding sites for miR-21, miR-181c, miR-181b, miR-31 and miR-7 and members of the network of commonly up- and downregulated genes with functional interactions to 11 blastema -associated genes. [score:7]
Morphological and histological studies of miR-21, miR-31 and/or miR-181 inhibition combined with identification of target genes would demonstrate their roles in blastema formation. [score:5]
The other three genes, bcl2l13, rgs5 and chka, were selected because we predicted them to be targeted by both miR-21 and miR-181c and they have inhibitory roles in cellular proliferation. [score:5]
Within this subset of differentially regulated zebrafish miRNAs, we identified 10 miRNAs: miR-21, miR-181c, miR-181b, miR-31, miR-7b, miR-2184, miR-24, miR-133a, miR-338 and miR-204, that showed conserved expression changes with both bichir and axolotl regenerating samples (Table 1). [score:4]
Interestingly, erb-b2 receptor tyrosine kinase 2 (erbb2) was the only blastema -associated transcript predicted to be targeted by one of the common regulated miRNAs, miR-181b and miR-181c. [score:4]
S21 Table Zebrafish Ensembl gene identifiers for 136 genes downregulated in three mo dels with predicted miRNA binding sites for miR-21, miR-181c, miR-181b, miR-31 or miR-7 in all three mo dels. [score:4]
STRING interactions with 11 common blastema -associated genes, miR-21, miR-31, miR-181, and 50 additional common differentially expressed genes with common predicted miRNAs binding sites. [score:3]
Next, we established a gene network for common miRNA target genes for miR-21, miR-31 and miR-181. [score:3]
In addition to rgs5, both bcl2l13 and chka had predicted binding sites for 4 miRNAs (miR-21, miR-181b, miR-181c and miR-7b). [score:1]
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[+] score: 77
DNMT3A (validated target of miR-29a-3p), BCL2 (validated target of both miR-34b-3p and miR-181c-5p), CCNE2 (validated target of miR-34b-3p) were downregulated only in SH-SY5Y (Figure 1). [score:10]
In silico analysis of DE miRNAs targets allowed to select four validated targets for both miR-29a-3p (CDK6, DNMT3A, DNMT3B, RAN) and miR-181c-5p (BCL2, GATA6, KIT, SIRT); five validated targets for miR-34b-3p (BCL2, CCNE2, CDK4, E2F3, MYB); four predicted targets for miR-517a-3p (IFNAR1, OLFM3, TNIP1, WEE1) (Supplementary Table S4). [score:9]
Expression profiling of candidate miRNAs in GI-ME-N, SK-N-BE(2)-C, SK-N-SH and SH-SY5Y revealed a statistically significant downregulation of miR-181c-5p and 517a-3p in all cell lines. [score:6]
MiR-181c-5p is a known tumor suppressor in neuroblastoma: it belongs to the miR-181 family, whose members are known to be upregulated after MYCN silencing [26, 27]. [score:6]
Moreover, by considering only neuroblastoma patients who showed relapse or progression of the disease and no MYCN amplification, lower expression of miR-181c was significantly associated with a worse prognosis (χ [2] = 8.29, df = 1, p-value = 4.0e-03, n = 120) (Figure 4C). [score:5]
Reduced expression of miR-181c is not significantly associated to a worse prognosis when considering the whole cohort of patients who undergo tumor progression event C. this relationship is significant when considering only the cases that progress and have no amplification of MYCN D. The cut off modus for miR-181c expression to draw Kaplan-Meier curves derives from the scan setting. [score:5]
Interestingly, Tumor Neuroblastoma - SEQC - 498 - RPM - seqcnb1 dataset analysis revealed that a decreased expression of miR-181c in neuroblastoma is linked to a worse overall survival (OS), either considering all neuroblastoma patients (χ [2] = 11.34, df = 1, p-value = 7.6e-04, n = 498) or selecting only cases with no MYCN amplification (χ [2] = 16.51, df = 1, p-value = 4.8e-05, n = 401) (Figure 4A, 4B). [score:3]
The link between miR-181c underexpression and poor outcome of neuroblastoma patients (found by querying public databases) suggests a potential prognostic value of this miRNA. [score:3]
Lower expression of miR-181c is related with a worse OS, either A. in the whole cohort of neuroblastoma samples or B. in only no amplified MYCN cases. [score:3]
Figure 4Lower expression of miR-181c is related with a worse OS, either A. in the whole cohort of neuroblastoma samples or B. in only no amplified MYCN cases. [score:3]
miR-181c expression and neuroblastoma patients' overall survival (OS). [score:3]
The same dataset did not show any significant variation in the expression of miR-181c-5p. [score:3]
In conclusion, our experimental data demonstrate that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are involved in neuroblastoma and are potential new therapeutic targets in neuroblastoma. [score:3]
Expression of miR-181c-5p and miR-517a-3p is known to be reactivated by 5′-AZA in gastric and bladder cancer, respectively [28, 29]. [score:3]
The analysis performed for different neuroblastoma stages showed a significant association between decreased expression of miR-181c and a worse overall survival of stage 4 neuroblastoma cases with no MYCN amplification (χ [2] = 7.17, df = 1, p-value = 7.4e-03, n = 116), but not with amplified MYCN (χ [2] = 1.7, df = 1, p-value = 0.192, n = 65) (Supplementary Figure S5). [score:3]
MiR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p regulate neuroblastoma cell viability. [score:2]
Expression profiling of 754 miRNAs, combined with methylation assays of specific CpG islands and in silico analyses, allowed us to focus on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p. [score:2]
We focused our analysis on 12 miRNAs (miR-22, miR-29a-3p, miR-34a, miR-126, miR-140-3p, miR-141, miR-181c-5p, miR-202, miR-455-5p, miR-508-3p, miR-517a-3p and miR-576-3p). [score:1]
Cells were transiently reverse -transfected with 30 pmoles of miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p mimics or equal amounts of scrambled molecules for 24h and 48h, by using siPORTNeoFX Transfection Agent (Ambion [®], Austin, TX), according to the manufacturer's instruction. [score:1]
Transfection with miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p mimics determined a significant decrease of cell viability, both in SK-N-BE(2)-C and in SH-SY5Y. [score:1]
The promoter of the genes encoding seven of them (miR-29a-3p, miR-34a, miR-126, miR-141, miR-181c-5p, miR-202 and miR-517a-3p) contained CpG islands, whose methylation significantly decreased after treatment with 5′-AZA (see later). [score:1]
Briefly, 1.2 x 10 [4] cells / well were reverse -transfected with miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p mimics or equal amounts of scrambled molecules and were grown for 24h and 48h. [score:1]
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[+] score: 73
In light of this, we presume that miR-181 upregulation is an important host protective mechanism against endotoxin shock, because it can shift the immune status from hyperinflammation to endotoxin tolerance via a rapid shutdown of inflammatory cytokine expression without altering anti-inflammatory cytokine expression. [score:8]
The miR-181 mimics also suppressed ouabain -induced TNF-α mRNA expression in A549 cells (Fig 3D) and TNF-α protein expression in human blood monocytes (Supplementary Fig S8A), miR-181d had the strongest effect. [score:7]
Furthermore, when siRNA was used to knock down Egr-1 expression, the ouabain -induced increase in pri-miR-181c/d, mature miR-181c, and mature miR-181d expression was attenuated (Fig 5C). [score:6]
Q-PCR analysis showed that miR-181b, miR-181c, and miR-181d were upregulated in sepsis patients, while miR-181a and miR-16 were unchanged (Fig 4E). [score:4]
Luciferase constructs with mutations in T55 were designated m1, m2, m3, m4, m5, m6, m7, FM (full mutation), and 181BSM (miR181 binding site mutation), respectively. [score:4]
The expression levels of pri-miR-181c/d, miR-181c, and miR-181d after Egr-1 siRNA transfection. [score:3]
To verify database predictions, we showed that “mimics” of miR-181a, miR-181b, miR-181c, and miR-181d inhibited the luciferase activity of a TNF-α 3′-UTR reporter (T789), but had no effect when the miR-181 binding site was mutated (T789 m) (Fig 3C, left panel). [score:3]
Figure 5 LPS and ouabain trigger miR-181c/d transcription through Egr-1 Ouabain and LPS induced miR-181s expression in human blood monocytes (left panel), THP-1 cells (middle panel), and A549 cells (right panel). [score:3]
LPS and ouabain trigger miRNA-181c/d transcription through Egr-1. Ouabain -induced HuR export plays a pivotal role in regulating TNF-α mRNA stability. [score:2]
To determine the role of the Egr-1 binding sites in miR-181c/d transcription, cells were transiently transfected with human miR181c/d promoter deletion (miR-181c/d P2) or mutation (miR-181c/d P1 m) constructs. [score:2]
Notably, miR-181d failed to alter the general ribosome profile and TNF-α mRNA distribution in polysomes (Supplementary Fig S9A–D), indicating that members of the miR-181 family specifically regulate TNF-α mRNA stability. [score:2]
A mutated version (T789 m) of this construct carrying a 7-bp substitution in the miR-181 binding site was obtained through site-directed mutagenesis. [score:2]
Therefore, we compared the expression of the miR-181 family members in human monocytes isolated from 25 patients with severe sepsis due to infections. [score:2]
In ouabain -treated cells, TNF-α mRNA stability was preferentially regulated by HuR and not by miR-181 family members. [score:2]
Thus, the AREs and the miR-181 binding site within the TNF-α 3′-UTR are cis-regulatory elements that are functionally dependent on each other. [score:2]
The microRNA181 family negatively regulates TNF-α mRNA stability and induces immunoparalysis. [score:1]
Construction of firefly luciferase reporter plasmid harboring miR-181c/d promoter and its mutants (left panel). [score:1]
Twenty-four hours later, these cells were stimulated with 100 nM ouabain for 2 h. Q-PCR analysis was performed to measure the expression levels of pri-miR-181c/d, miR-181c, and miR-181d. [score:1]
Taken together, these results indicate that Egr-1 plays an important role in miR-181c/d transcription. [score:1]
Luciferase activity in A549 cells transfected with constructs encoding vector T789-Luc or T789 m-Luc of TNF-α 3′-UTR plus mimics of miR-181a, miR-181b, miR-181c, miR-181d (left panel), or antagomir-181 (right panel). [score:1]
In fact, only one miR-181 binding site is present in the minimal TNF-α 3′-UTR (T55); in contrast, seven “AUUUA” motifs are located in the immediate vicinity of the miR-181 binding site. [score:1]
Chromatin immunoprecipitation (ChIP) analysis confirmed that Egr-1 associated with the miR-181c/d promoter after LPS treatment (Fig 5D). [score:1]
The vector miR-181c/d P2 (CDP2) was created from CDP1 by deleting the 450-bp upstream sequence containing the three Egr-1 binding sites. [score:1]
Notably, miR-181 binding sites are frequently distributed in the 3′-UTRs of many inflammatory cytokines, including IL-1α and TNF-α; surprisingly, no miR-181 binding sites have been found in the 3′-UTRs of anti-inflammatory cytokines such as IL-10 and TGF-β. [score:1]
The microRNA181 family consists of four members: miR-181a, miR-181b, miR-181c, and miR-181d. [score:1]
Three potential early growth response protein 1 (Egr-1) binding sites are present between nucleotides −993 and −949 in the human miR-181c/d promoter (Fig 5B, left panel). [score:1]
However, the miR-181c/d cluster is located in an intergenic region on chromosome 19, and miR-181d is slightly downstream of miR-181c (Supplementary Fig S12A). [score:1]
miR-181c and miR-181d are co-transcribed (Supplementary Fig S12B and C). [score:1]
The luciferase activity (firefly/ Renilla) of cells transfected with miR-181c/d promoter or its mutant (right panel). [score:1]
Here, we showed that members of the miR-181 family act downstream of TLR4 signaling to induce TNF-α mRNA degradation. [score:1]
Therefore, it is likely that the binding of HuR to the 3′-UTR of TNF-α triggers a conformational change in the local RNA that masks the miR-181 binding site. [score:1]
As expected, the increases in miR-181c/d promoter activity induced by ouabain (Fig 5B, right panel) or LPS (Supplementary Fig S12D) were attenuated when the Egr-1 binding sites were mutated or deleted. [score:1]
The transcriptional start site of miR-181c was previously determined using 5′-RACE (Hashimoto et al, 2010). [score:1]
Because the miR-181 binding site in the 3′-UTR of TNF-α is located within two adjacent “AUUUA” motifs (Supplementary Fig S14A), we speculated that, after ouabain treatment, HuR might counteract the destabilizing effect of miR-181d on TNF-α mRNA. [score:1]
The human miR-181c/d promoter reporter vector was designated miR-181c/d P1 (CDP1). [score:1]
The vector miR-181c/d P1m (CDP1m) was generated from CDP1 by mutating the three Egr-1 binding sites to “ATCATAATC”. [score:1]
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[+] score: 69
We then tested how miR-181c upregulation affected cell proliferation and apoptosis, because the upregulation of PCAF and p53 protein levels in U251 cells could lead to activation of a plethora of other downstream tumor suppressive genes that can suppress the oncogenic state of these glioma cells. [score:11]
Concluding, the positive correlation of miR-181c with these two tumor suppressor genes can potentially explain the inhibitory effect of miR-181c on cell growth and the more subtle increase in apoptosis observed in the glioma cells (Figure8). [score:5]
The upregulation of PCAF in response to increased miR-181c could occur through a known transactivator of PCAF, p53 [12], [13]. [score:4]
Lower levels of miR-181c in glioblastomas could indirectly decrease the transcript levels of the positively correlated PCAF, resulting in decreased activation of major tumor suppressive pathways in glioblastoma cells. [score:4]
We performed western blot analysis to verify the increase of PCAF protein levels in response to miR-181c upregulation in U251 cells and in an additional glioma line, U87. [score:4]
There was ∼12% (p<0.05, t-test) increase in Caspase-3/7 activity in response to miR-181c upregulation relative to the negative control (Figure7B). [score:4]
Interestingly, miR-181c has been reported to be low in a panel of high-grade glioblastomas tumors and glioblastomas cell lines [18] and inhibition of another member of the miR-181 family, miR-181a, in A549 lung carcinoma cells induced cell growth [19]. [score:3]
0000804.g008 Figure 8Tumor suppressive pathway involving miR-181c. [score:3]
Tumor suppressive pathway involving miR-181c. [score:3]
0000804.g009 Figure 9 Validation experiments allowed us to infer a tumor suppression pathway involving miR-181c (Figure8). [score:3]
The validation experiment suggested that the direction of causality very likely went from miR-181c to PCAF (although if the pair is networked as a negative feedback loop in cis, causality in vivo could be bi-directional). [score:3]
From these data sets, we inferred and validated a tumor suppression pathway linked to miR-181c. [score:3]
U251 cells were transfected with 50 nM of pre- miR-181c (Ambion) and 50 nM of negative control scramble (Ambion) and seeded in 96-well plates at 10,000 cells/well. [score:1]
We checked the levels of p53 in both U251 and U87 treated cells and observed a significant increase of p53 protein levels in the miR-181c treated U251 cells (Figure6C,D); however we could not detect p53 in the U87 cells. [score:1]
0000804.g005 Figure 5The above figure represents Ct [scrambled]-Ctpre-mir/2′ -O-Me from three individual transfection experiments of pre- miR-181c, pre- miR-182, 2′ -O-Me- miR-19a, 2′ -O-Me-scrambled and pre-mir-scrambled. [score:1]
Twenty-four hours after the transfections of pre- miR-182, pre- miR-181c, 2′ -O-Me- miR-19a, as well as a pre-miR scramble or a 2′ -O-Me scramble, we collected total RNA for real-time RT-PCR to determine the relative changes in the levels of the correlated mRNAs (Figure5). [score:1]
We determined that miR-181c leads to an increase in PCAF and p53 protein levels consistent with the known positive interactions between PCAF and p53 (Figure6). [score:1]
0000804.g007 Figure 7U251 cells were treated with pre- miR-181c and negative control scramble. [score:1]
However, the level of apoptosis that we observed does not fully account for the much higher difference in the viable cell numbers, suggesting that miR-181c is also having an anti-proliferative effect which could be mediated through p53 and PCAF (Figure8). [score:1]
Immunoblot analysis of miR-181c treated cells. [score:1]
Three independent transfections were performed for each pre-mir and 2′ -O-Me oligoncleotide of miR-181c, miR-182, miR-19a and a scrambled pre-miR or 2′ -O-Me as a negative control (Ambion, TX). [score:1]
miR-181c and miR-182 were individually transfected as pre-miRNAs into U251 glioblastoma cells to increase their levels 2–4 fold (data not shown). [score:1]
Among the validated high correlation pairs was a positive correlation between miR-181c and p300/CBP -associated factor (PCAF). [score:1]
Relative Apoptosis/Cell growth was determined by comparing miR-181c with scramble treated cells. [score:1]
The above figure represents Ct [scrambled]-Ctpre-mir/2′ -O-Me from three individual transfection experiments of pre- miR-181c, pre- miR-182, 2′ -O-Me- miR-19a, 2′ -O-Me-scrambled and pre-mir-scrambled. [score:1]
Three miRNAs (miR-181c, miR-182, miR-19a) were selected from among the miRNA-mRNA high correlation pairs to test whether the correlations predicted changes that could be reproduced experimentally. [score:1]
Immunoblots of U251 and U87 transfected cells transfected with either miR-181c pre-miRNA or a scrambled sequence. [score:1]
We observed ∼30% (p<0.01, t-test) decrease in viable cells in the miR-181c treated sample, relative to the negative control (Figure7A). [score:1]
U251 cells were treated with pre- miR-181c and negative control scramble. [score:1]
0000804.g006 Figure 6Immunoblot analysis of miR-181c treated cells. [score:1]
These results suggest that the decrease of cell numbers with miR-181c addition could be partially explained by increased apoptosis. [score:1]
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13
[+] score: 64
Other miRNAs from this paper: hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-30a, hsa-mir-32, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-107, hsa-mir-129-1, hsa-mir-30c-2, hsa-mir-139, hsa-mir-204, hsa-mir-212, hsa-mir-181a-1, hsa-mir-222, hsa-mir-15b, hsa-mir-23b, hsa-mir-132, hsa-mir-138-2, hsa-mir-140, hsa-mir-142, hsa-mir-129-2, hsa-mir-138-1, hsa-mir-146a, hsa-mir-154, hsa-mir-186, rno-mir-324, rno-mir-140, rno-mir-129-2, rno-mir-20a, rno-mir-7a-1, rno-mir-101b, hsa-mir-29c, hsa-mir-296, hsa-mir-30e, hsa-mir-374a, hsa-mir-380, hsa-mir-381, hsa-mir-324, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-15b, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19b-2, rno-mir-19a, rno-mir-21, rno-mir-23a, rno-mir-23b, rno-mir-24-1, rno-mir-24-2, rno-mir-27a, rno-mir-29c-1, rno-mir-30e, rno-mir-30a, rno-mir-30c-2, rno-mir-32, rno-mir-92a-1, rno-mir-92a-2, rno-mir-93, rno-mir-107, rno-mir-129-1, rno-mir-132, rno-mir-138-2, rno-mir-138-1, rno-mir-139, rno-mir-142, rno-mir-146a, rno-mir-154, rno-mir-181c, rno-mir-186, rno-mir-204, rno-mir-212, rno-mir-181a-1, rno-mir-222, rno-mir-296, rno-mir-300, hsa-mir-20b, hsa-mir-431, rno-mir-431, hsa-mir-433, rno-mir-433, hsa-mir-410, hsa-mir-494, hsa-mir-181d, hsa-mir-500a, hsa-mir-505, rno-mir-494, rno-mir-381, rno-mir-409a, rno-mir-374, rno-mir-20b, hsa-mir-551b, hsa-mir-598, hsa-mir-652, hsa-mir-655, rno-mir-505, hsa-mir-300, hsa-mir-874, hsa-mir-374b, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-874, rno-mir-17-2, rno-mir-181d, rno-mir-380, rno-mir-410, rno-mir-500, rno-mir-598-1, rno-mir-674, rno-mir-652, rno-mir-551b, hsa-mir-3065, rno-mir-344b-2, rno-mir-3564, rno-mir-3065, rno-mir-1188, rno-mir-3584-1, rno-mir-344b-1, hsa-mir-500b, hsa-mir-374c, rno-mir-29c-2, rno-mir-3584-2, rno-mir-598-2, rno-mir-344b-3, rno-mir-466b-3, rno-mir-466b-4
These miRNAs were chosen as representative of the different patterns that were observed: up-regulation (miR-21-5p) or down-regulation (miR-222-3p) during latency; up-regulation (miR-181c-5p) or down-regulation (miR-500-3p) in the chronic period; up-regulation (miR-146a-5p) or down-regulation (miR-551b-3p) in the entire course of the disease. [score:21]
Continuing modifications in the expression pattern of miRNAs in the course of chronic epilepsy support the hypothesis that epileptogenesis is a dynamic process that continues even after the initial diagnosis of the disease, i. e. after the initial spontaneous seizures 1. The comparison between chronic epileptic rats and the human cases identified four miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that are similarly up-regulated in expression levels in both species. [score:10]
Continuing modifications in the expression pattern of miRNAs in the course of chronic epilepsy support the hypothesis that epileptogenesis is a dynamic process that continues even after the initial diagnosis of the disease, i. e. after the initial spontaneous seizures 1. The comparison between chronic epileptic rats and the human cases identified four miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that are similarly up-regulated in expression levels in both species. [score:10]
Some miRNAs (miR-129-1-3p; miR-129-2-3p, miR-129-5p, miR181c-5p, miR181d-5p, miR-409a-5p, miR-655 and miR-874-3p) were up-regulated (Fig. 2, Supplementary Fig. S3A), whereas others (miR-296-5p, miR-500-3p and miR-652-3p) were down-regulated only in the chronic phase, while not being significantly altered during latency (Fig. 2, Supplementary Fig. S3B). [score:7]
Second, the chronic phase was accompanied by significant alterations in miRNA expression in the rat GCL, and comparison with data from epileptic patients identified several miRNAs (notably miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that were up-regulated in both human and rat epileptic hippocampus. [score:6]
We identified four miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that were up-regulated in both epileptic humans and rats (Table 1). [score:4]
Even if displaying the same patterns observed with the microarray, the expression levels of mir-181c-5p, miR-433-3p, miR-505-3p and miR-551b-3p were not significantly different from controls (Fig. 4). [score:3]
Cluster 4 included miR-181c-5p and miR-181d-5p. [score:1]
As for miR-181c-5p, it was highlighted by network analysis in cluster 4, and implicated in cytokine-cytokine receptor interaction and in the inflammatory response. [score:1]
Cluster 3 (that includes miR-142-3p and miR-146a-5p) and cluster 4 (including miR-181c-5p and miR-181c-5p) are connected to the “cytokine-cytokine receptor interaction” signaling pathway, which suggests a neuroinflammatory role for those miRNAs. [score:1]
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14
[+] score: 43
We focused on three differentially expressed miRNA: miR-181C, miR-15a and miR-20b, which were found to be down-regulated in a diabetic-like environment and up-regulated after the addition of calcitriol. [score:9]
MiR-15a, miR-20b and miR-181C were found to be down-regulated in a diabetic-like environment and up-regulated after the addition of calcitriol; they were chosen for further investigation at the level of their gene targets, which have been shown to be involved in the modulation of endothelial function. [score:7]
MiR-126, miR-411, miR-20b, miR-15a and miR-181c were down-regulated under diabetic conditions and over-expressed after calcitriol was added. [score:6]
We found that genes targets from the Kruppel-like family, which are transcription factors that play key regulatory roles in cellular growth, differentiation, proliferation, apoptosis and angiogenesis [20, 21], take part as putative targets for miR-181C and miR-20b. [score:6]
Becker et al. [33] demonstrated that under the influence of anabolic steroids, miR-181c was down-regulated in bovine liver and might lead to uncontrolled proliferation in the liver. [score:4]
Gene target and pathway analysis of miR-181C, miR-15a and miR-20b. [score:3]
In order to determine the potential genes involved in HUVEC exposed to a diabetic-like environment and calcitriol, we analyzed the predicted target genes of these 3 miRNA (miR-15a, miR-20b and miR-181c). [score:3]
Using pediatric cancer stem cells, Sanchez-Diaz et al. [37] showed that miR-181c regulate cell proliferation and the cell cycle, probably by affecting the Notch signaling pathway and the bone morphogenetic protein (BMP) pathway. [score:2]
From the miRNA list presented in Table  1 and from the corresponding Venn diagram (Figure  1C), we validated several miRNA (marked in bold in Table  1) that are known to be modified in a diabetic environment (miR-510, miR-15a, miR-20b, miR-126, and miR-181C). [score:1]
MiR-181c, miR-15a, miR-20b, miR-411, miR-659, miR-126 and miR-510 were selected for further analysis because they are known to be modified in DM and in other biological disorders. [score:1]
In addition, 10 [-10] mol/l calcitriol was given to the cells 1 h after stimulation for an additional 23 h. The miRNA set that included (A) miR-659, (B) miR-510, (C) miR-181C, (D) miR-411, (E) miR-126, (F) miR-15a, and (G) miR-20b was validated using real time PCR. [score:1]
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15
[+] score: 41
In this study, we report that lncRNA by competitively binding the miR-181 family, upregulating Bcl-2, and then suppressing gastric carcinogenesis (Fig.   5d). [score:6]
Furthermore, ectopic expression of MEG3 in HGC-27 and MGC-803 cells inhibited cell proliferation, migration, invasion, and promoted cell apoptosis, which might be due to MEG3 sequestering oncogenic miR-181 s in GC cells. [score:5]
Furthermore, MEG3 affected GC cell phenotypes in a miR-181 sites -dependent manner, which occurs without changes in the levels of miR-181 isoforms, suggesting that MEG3 regulates miR-181 activity by altering miRNA targeting. [score:4]
These findings suggest that lncRNA MEG3, a ceRNA of miR-181 s, could regulate gastric carcinogenesis and may serve as a potential target for antineoplastic therapies. [score:4]
We also showed that MEG3 inhibited GC cell proliferation, migration and invasion by operating as a competing endogenous RNA (ceRNA) for the miR-181 microRNA (miRNA) family. [score:3]
b The expression of MEG3 and Bcl-2 mRNA in HGC-27 cells transfected with empty vector, wild type MEG3 or mutant MEG3 as indicated; c Immunoblot analysis of Bcl-2 protein in HGC-27 cells transfected with empty vector, wild type MEG3 or mutant MEG3 as described in B; d A Schematic mo del of MEG3/miR-181/Bcl-2 cascade in gastric carcinogenesis. [score:3]
Taken together, our research demonstrated that MEG3 acted as a key regulator in human gastric carcinogenesis and revealed roles of MEG3 in regulating miR-181-Bcl2 axis. [score:3]
Studies have reported that miR-181 targets multiple Bcl-2 family members in astrocytes [24]. [score:3]
Subsequently, we constructed a series of luciferase reporters containing the wild type MEG3 (pMIR-MEG3-WT), or mutant MEG3 with mutations of single (pMIR-MEG3-MUT1, 2, 3, 4) or all four predicted miR-181 binding sites (pMIR-MEG3-MUT1-4). [score:2]
The miR-181 family contains four miRNAs (miR-181a/b/c/d), which are transcribed from three separated gene loci. [score:1]
The lower panel: the prediction for miR-181 s binding sites on MEG3 transcript. [score:1]
MEG3 is physically associated with miR-181 family. [score:1]
Among the results, we found 4 miR-181 family binding sites scattering the MEG3 transcripts, suggesting its ceRNA potential for miR-181 s (Fig.   3a). [score:1]
Fig. 3The interaction of MEG3 with miR-181. [score:1]
We found that transfection of HGC-27 cells with miR-181a mimic reduced the luciferase activities of the MEG3-WT reporter vector but not empty vector or all miR-181 site mutant reporter vector (Fig.   3b), suggesting the binding of miR-181a to these sites. [score:1]
a The upper panel: schematic outlining the predicted binding sites of miR-181 s on MEG3. [score:1]
The red nucleotides are the complementary sequences to miR-181 seed sequences. [score:1]
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16
[+] score: 39
In this study, to validate multiple-to-multiple relationships between miRNAs and targets in cancer cells, we demonstrated that two pairs of multiple miRNAs, miR-224 and -452, and miR-181c and -340, had multiple target genes and synergistically decreased cell proliferation through regulation of their targets in human GC cells. [score:8]
Here, we focus on four miRNAs, miR-152, -181c, -224 and -340, because we have already reported that miR-181c is epigenetically down-regulated in GC [13] and CpG islands are located in the upstream regions of three other miRNAs (Figure 2A and C, and Figure S1). [score:4]
On RT-PCR analysis, KRAS and MECP2 were found to be down-regulated by miR-340 and miR-181c alone, or combinational transfection in KATO-III cells (Figure 6B). [score:4]
When miR-340 and miR-181c were transfected into KATO-III cells, proliferation was synergistically down-regulated by two miRNAs (Figure 6A). [score:4]
To determine whether or not epigenetically regulated miR-340 and miR-181c co-operatively affect their targets, we analyzed the mRNA levels of KRAS and MECP2. [score:4]
We previously reported that miR-181c down-regulated NOTCH4 too [13]. [score:4]
To examine the possibility of multiple-to-multiple relationships between miRNAs and targets in cancer cells, we focused on two combinations of miRNAs in GC cells, the miR-224/−452 cluster, and miR-181c and -340, in this study. [score:3]
For instance, DPYSL2 (dihydropyrimidinase-like 2, also known as collapsing response mediator protein 2, CRMP2) is targeted by miR-224, -452, and -181c, KRAS by miR-224, -452, -181c, -340 and -152, and MECP2 (methyl CpG binding protein 2) by miR-181c and -340, respectively (Figure 3). [score:3]
We found that the two sets of miRNAs, miR-224 and -452, and miR-181c and -340, had multiple target genes, DPYSL2 and KRAS, and KRAS and MECP2, respectively, and synergistically decreased cell proliferation in human GC cell lines. [score:3]
Similarly, we found that miR-181c methylation is associated with gastric carcinogenesis via regulation of oncogenic genes KRAS and NOTCH4 [13]. [score:2]
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[+] score: 34
In order to mitigate the observed off- target transgene expression in ganglion cells following intravitreal delivery of hGRK1-containing AAV vectors, we incorporated a target sequence for miR181, an miRNA shown to be expressed exclusively in ganglion cells and inner retina into our AAV vectors (Atlas of miRNA distribution: http://mirneye. [score:9]
Similar to methods previously described, [32] we further restricted transgene expression to PRs by incorporating multiple target sequences for miR181, an miRNA endogenously expressed in cells of the inner and middle retina. [score:7]
At 4 weeks post-intravitreal injection, funduscopy and IHC on frozen retina cross sections revealed that addition of miR181c to the vector construct did eliminate off-target expression (Figure 7). [score:5]
A microRNA expression atlas of the mouse eye [55] indicates that miR-181c is highly expressed in retinal ganglion cells and middle retina and absent in photoreceptors in P60 mouse (http://mirneye. [score:5]
Although hGRK1-GFP-miR181c -mediated GFP expression was exclusive to PRs, it was also appreciably decreased (Figure 7). [score:3]
0062097.g007 Figure 7. Both hGRK1-GFP and hGRK1-GFP-miR181c were packaged in AAV2(quadY-F+T-V) and delivered intravitreally to C57BL/6 mice (1.5×10 [10] vg). [score:1]
php?state=P60&mirna=mmu-miR-181c). [score:1]
Both hGRK1-GFP and hGRK1-GFP-miR181c were packaged in AAV2(quadY-F+T-V) and delivered intravitreally to C57BL/6 mice (1.5×10 [10] vg). [score:1]
Both hGRK1-GFP and hGRK1-GFP-miR181c were packaged in AAV2(quadY−F+T−V) and delivered intravitreally to C57BL/6 mice (1.5×10 [10] vg). [score:1]
A hGRK1-GFP-miR181c construct was also generated and packaged in AAV2(quad Y−F+T−V) by inserting four tandem copies of complementary sequence for mature miR-181 (5′ ACTCACCGACAGGTTGAA 3′) (Atlas of miRNA distribution: http://mirneye. [score:1]
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[+] score: 34
miR-181 inhibits differentiation of AML cells into granulocytes and macrophages by down -regulating their direct targets PRKCD, CTDSPL, and CAMKK1 and then affecting the PRKCD-P38-C/EBPα pathway and reducing pRB phosphorylation. [score:7]
Expression of all miR-181 family members was reduced in adult AML patients (M1-M3 subtypes), suggesting all function as tumor suppressors. [score:5]
The in vivo expression of miR-181 partially reversed the lack of myeloid differentiation in AML patients and in the mice with CD34 [+] HSPCs from AML patients [37] It has been demonstrated that, in normal hematopoiesis, some miRNAs were involved in progenitor lineage commitment[38] and controlling HSC [39- 41] by coordinate repression of multiple targets [42]. [score:5]
The down-regulation of miR-181 was associated with leukemia invasiveness, and miR-181 has been well studied to be a prognostic predictor of AML [6, 36, 96, 97]. [score:4]
In AML CD34 [+] HSPC xenograft mice, inhibition of miR-181 increased differentiation of myeloid progenitors, reduced engraftment and infiltration of leukemic HSPCs into bone marrow and spleen, and ameliorated symptoms of leukemia. [score:3]
Su et al [37] demonstrated that miR-181 inhibition is a potential new treatment strategy for AML. [score:3]
These findings suggest that miR-181 is a potential target for AML therapy. [score:3]
Knockdown of miR-181 in cultured bone marrow blasts from AML patients partially reversed blockage of myeloid differentiation. [score:2]
Accumulating evidence indicates that the miR-181 family plays important roles in AML pathogenesis [36]. [score:1]
These results demonstrate critical but complex roles of miR-181 in AML, and more importantly, the temporal changes of miRNA expression and function during AML progression highlight a rigorous evaluation of miRNA -based therapy in AML. [score:1]
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[+] score: 32
miR-181, miR-183 and miR-200 miRNAs Families Members are Similarly down-regulated during in vitro DecidualizationInterestingly, three miRNAs families (miR-181, miR-183 and miR-200) were down-regulated during the decidualization process. [score:7]
miR-181, miR-183 and miR-200 miRNAs Families Members are Similarly down-regulated during in vitro Decidualization. [score:4]
The molecular pathways potentially regulated by the mir-181, miR-200 and miR-183 families with the potential target genes are listed below the histograms. [score:4]
Interestingly, three miRNAs families (miR-181, miR-183 and miR-200) were down-regulated during the decidualization process. [score:4]
For the mir-181 family, which includes six miRNAs precursors (mir-181a-1, mir-181a-2, mir-181b-1, mir-181b-2, mir-181c and mir-181d) located at three different loci (chromosomes 1, 9 and 19), the corresponding mature miRNA expression in decidual cells decreased (Figure 1B). [score:3]
By using the Diana miR-Path database [21], we searched for the molecular pathways potentially regulated by the mir-181 family. [score:2]
The top two molecular pathways potentially regulated by the miR-181 family are TGFß signaling and T cell receptor. [score:2]
Another interesting finding is that all the members of three different miRNAs families (miR-181, miR-200 and miR-183) have been identified to be similarly regulated. [score:2]
B, miR-181 C, miR-200 and D, miR-183 family members’ expression in the E+P decidualized hESCs for 9 days if compared to the non decidualized control hESCs. [score:2]
miR-181, miR-183 and miR-200 miRNAs families members are similarly regulated during in vitro decidualization. [score:2]
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[+] score: 27
The sequences for control and miR-181a inhibitors were as follows: control inhibitor, 5′-CAGUACUUUUGUAGUACAA-3′ and miR-181 inhibitor, 5′-ACUCACCGACAGCGUUGAAUGUU-3′. [score:7]
MiR-181a down-regulates triglycerides and total cholesterol levels in vivoWe have recently characterized the inhibitory function of miR-181 in the regulation of embryo implantation in mice (unpublished data). [score:5]
The findings that IDH1 is a direct target of miR-181 and the opposite phenotypes displayed by miR-181a TG and IDH1 TG mice led us to test the possibility that miR-181a may regulate lipid metabolism through IDH1. [score:5]
To knockdown miR-181a in mice, six-week old miR-181 WT male mice were given administration of nanoparticles packed with either control or miR-181a inhibitors four times at one-week intervals 33. [score:4]
To determine whether miR-181a is involved in the regulation of lipid metabolism, six-week old miR-181 TG and WT male mice were fed with high fat diet (HFD) for 10 weeks. [score:2]
To explore whether miR-181a is involved in the regulation of lipid metabolism, both miR-181 TG and WT mice were fed with high fat diet (HFD), and after 10 weeks of feeding, miR-181a TG mice exhibited smaller size and lower body weight than miR-181a WT mice (Figures 1A and 1B) while these mice showed no obvious differences in food intake (Supplementary Figure S1B). [score:2]
We have recently characterized the inhibitory function of miR-181 in the regulation of embryo implantation in mice (unpublished data). [score:2]
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21
[+] score: 26
First, the heterogeneity existed in our meta-analysis and was probably due to the differences in baseline demographic characters of population, the tumor types, the disease stages, the cut-off value of miR-181 expression, the duration of follow-up, etc. [score:5]
For instance, miR-181a and miR-181c have only one-nucleotide difference in their mature miRNA sequences, but only miR-181a can promote CD4 and CD8 double -positive (DP) T cell development, when ectopically expressed in thymic progenitor cells. [score:4]
MiR-181 family is one of those miRNA families, which generally express in 70 species and various human cancers [6]. [score:3]
In recent years, the miR-181 family was found dysregulated in a variety of human cancers and significantly associated with clinical outcome of cancerous patients. [score:2]
These findings indicated the significance of miR-181 in human hematopoietic development. [score:2]
MiR-181 preferably expresses in hematopoietic cell lineages and is involved in erythropoiesis, granulocytic and megakaryocytic differentiation [33]– [36]. [score:2]
The distinct activities of miR-181a and miR-181c are largely determined by their unique pre-miRNA loop nucleotides [28]. [score:1]
For PubMed, the contextual query language (CQL) was “ (mir-181[Title/Abstract]) OR (microRNA-181[Title/Abstract]) OR (mir-181a[Title/Abstract]) OR mir-181b[Title/Abstract]”; for EMBASE, the CQL was “(mir-181 or microRNA-181 or mir-181a or mir-181b). [score:1]
This family includes 4 members (miR-181a, miR-181b, miR-181c and miR-181d) and they are highly conserved in the seed-region sequence and RNA secondary structure. [score:1]
Forest plots of studies evaluating HR of overall survivals comparing high and low miR-181 expression. [score:1]
The importance of miR-181 in hematopoiesis leaded most studies to focus on the role of miR-181 family in hematological malignancies. [score:1]
First, lack of abundant miR-181a/b expression data in global population makes it difficult to set a standard value for the measurement of miR-181/b. [score:1]
Most of the studies used quantification real-time PCR to measure the expression level of miR-181 (TaqMan: 6 and Stem-loop: 2), and others used microarray method. [score:1]
In recent years, miR-181 family has been found associated with tumorigenesis. [score:1]
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[+] score: 24
The miR-181 family is particularly enriched in the brain and is involved in autism spectrum disorders [56], schizophrenia [57], Alzheimer disease [58], where they are mainly found to be upregulated. [score:6]
Note that prenatal stress downregulated miR-181 and miR-186 expression in the frontal cortex. [score:6]
Downregulation of miR-181 contributes to accelerated HIV -associated dementia in opiate abusers [59]. [score:4]
Downregulation of miR-181 was shown to have protective effects against apoptosis and mitochondrial dysfunction [60]. [score:4]
At the cellular level, miR-181 regulates apoptosis factors such as bcl-2 in astrocytes. [score:2]
miR-181 and miR-186 were chosen for verification using qRT-PCR analysis. [score:1]
Stress also led to critical decreases in let-7c, miR-23b, miR-181, and miR186 amounts. [score:1]
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23
[+] score: 24
At the same time, up-regulation of hsa-miR-181c and hsa-miR-182 targets HRB and IGF1R expression, suggesting the biological functions of the two key genes may be suppressed. [score:10]
In contrast, the miRNAs hsa-miR-340 (14 degrees), hsa-miR-181c (11 degrees) and hsa-miR-182 (10 degrees) were significantly up-regulated in the DCM samples. [score:4]
In addition, has-miR-181c and has-miR-10a showed a trend towards higher expression levels in DCM samples (P > 0.05). [score:3]
Androulidaki et al. [36] found that miRNA-181c was involved in the lipopolysaccharide role of the macrophage inflammatory reaction by regulating Akt1. [score:2]
In addition, hsa-miR-181c (P > 0.05) and hsa-miR-10a (P > 0.05) exhibited a trend of higher expression levels in DCM samples, but these differences did not reach statistical significance when compared with control samples (Fig. 9). [score:2]
The key miRNAs identified included hsa-miR-181c, hsa-miR-19a and hsa-miR-19b, which all have higher degrees in the network diagram. [score:1]
Selected miRNAs (hsa-miR-10a, miR-19b, miR-181c, miR-302d and miR-340) were further quantified with TaqMan qRT-PCR. [score:1]
The miRNAs hsa-miR-200b (16 degrees), hsa-miR-181c (14 degrees), hsa-miR-340 (13 degrees), hsa-miR-557 (13 degrees), hsa-miR-19a (12 degrees), hsa-miR-19b (12 degrees) and hsa-miR-548f (12 degrees) were significantly differentially regulated in DCM samples compared with non-failing control samples. [score:1]
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24
[+] score: 23
Specifically, miR181-a is present in both bovine oocytes and embryos with increased expression in early stages of development then drops to low levels in the blastocyst and is thought to regulate nucleoplasmin2 a protein important in nuclear organization (Lingenfelter et al., 2011). [score:5]
Activin and TGF beta regulate expression of the microRNA-181 family to promote cell migration and invasion in breast cancer cells. [score:4]
Cutting edge: microRNA-181 promotes human NK Cell development by regulating notch signaling. [score:3]
MiR-181 and miR-370 were found to be expressed in the control media regardless of BSA supplementation (Table 3). [score:3]
When BSA was not supplemented in SOF media, miR-181 showed expression though right at threshold cut off in one blastocyst pool and was not detected in the second pool making the data not conclusive. [score:3]
In BSA supplemented media, the expression of both miR-181 and miR-370 was detected though not statistically significantly different between embryos of varying quality or above the baseline control. [score:3]
MiR-181 has been associated with roles in genes relating to cancer (Neel and Lebrun, 2013), immune function through NK cell development (Cichocki et al., 2011) and embryonic development (Lingenfelter et al., 2011). [score:2]
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[+] score: 23
Overexpression of pre-miR-363 had no effect on expression of any of the other cardiac transcription factors tested, and overexpression of pre-miR-181a or -miR-181c had no effect on any of the cardiac transcription factors tested (Figure 7). [score:7]
We studied the temporal and spatial expression patterns of four miRNAs in differentiating hESCs, and found that expression of miRNA (miR)-363, miR-367, miR-181a, and miR-181c was specific for stage and site. [score:5]
In contrast, introduction of pre-miR-181a and pre-miR-181c had no detectable effect on HAND gene expression (Figure 3A). [score:3]
In contrast, luciferase activity from either reporter was not affected by pre-miR-181a or pre-miR-181c expression. [score:3]
BMP4 stimulation also induced the expression of endogenous miR-363 and miR-181c, but not miR-367 or miR-181a (Figure 6B). [score:3]
Process miR-363 miR-367 miR-181a miR-181c miR-1     (PcT score) (PcT score) (PcT score) (PcT score) (PcT score)GATA6 (18)Regulate terminal differentiation/proliferationNpNpACUUACAa (0.52)ACUUACAa (0.52)NpNKX2.5 (5)Commitment to myocardial lineageNpNpACUUACAa (0.52)ACUUACAa (0.52)NpHAND1 (5)Left ventricular cardiac morphogenesis, giant cell differentiationCACGUUAa (0.78)CACGUUAa (0.78)NpNpNp HAND2 (4) Cardiac morphogenesis, particularly right ventricle and aortic arch CACGUUAa (0.76) CACGUUAa (0.76) ACUUACAa (0.52) ACUUACAa (0.52) Np Np, No pairing. [score:2]
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26
[+] score: 23
This miRNA regulates the expression of the cell cycle regulator p27 [kip1], which is normally induced during monocytic differentiation, thus ectopic expression of miR-181 counteracts monocytopoiesis [54]. [score:7]
Increased expression levels of miR-181 were associated with favourable outcome in AML with both normal and abnormal karyotypes [75, 104, 105], and connected with CEBPA mutations [105]. [score:4]
In this case, the downregulation of the miR-181 family was suggested to contribute to an aggressive leukemia phenotype through mechanisms associated with the toll-like receptors and interleukin-1 β  [73]. [score:4]
Among the deregulated miRNAs in AML, these studies identified miRNAs already known to be hematopoietic specific (e. g., miR-142-5p, miR-223, and miR-181) or reported to be highly expressed in other hematological malignancies and solid tumours (e. g., miR-221, miR-222, miR-17-92 cluster and miR-155) [6, 18, 20, 21, 69]. [score:4]
Conversely, miR-181 levels are decreased by VitD3 treatment [54]. [score:1]
In contrast, in different studies performed on a high-risk subgroup with normal karyotype, decreased levels of miR-181 were identified [73]. [score:1]
Microarray analysis identified different miRNAs modulated during monocytic differentiation of AML cell lines, in particular miR-424, miR-32, and miR-181 [49– 51]. [score:1]
Increased miR-181 levels characterized these leukemias [71], a miRNA known to be involved in lymphoid lineage differentiation and to inhibit monocytopoiesis [18, 54]. [score:1]
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27
[+] score: 23
MiR-181c expression was up-regulated after 5-aza-2′-deoxycytidine hypomethylating treatment, indicating that miR-181c may be silenced through methylation. [score:6]
MiR-181c was shown to directly target KRAS and exhibited a weak expression in gastric carcinoma [60]. [score:5]
This result indicates that, as for miR-181c, miR-433 down-regulation is mediated through methylation epigenetic silencing. [score:4]
In addition, KRAS was shown to be targeted by miR-181a in oral squamous cell carcinoma, by miR-181c in gastric carcinoma, and by miR-181d in glioma. [score:3]
Other members of the miR-181 family (with a similar seed sequence) have also been described to target KRAS mRNA. [score:3]
These observations emphasized the role of miR-181 family as a major negative regulator of the RAS-MAPK pathway in cancer. [score:2]
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[+] score: 20
[21] Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
[21]Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
[30] Three of the downregulated miRNAs (miR-148a, miR-181c and miR-210) are normally highly expressed during lactation in the mouse mammary gland. [score:6]
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29
[+] score: 20
hESC were transfected with a miR-181a inhibitor or a miRNA inhibitor negative control (miRNA inhibitor control, 100 nM) for 24 h, and then cells were treated with or without 0.5 mM 8-Br-cAMP and 1 μM MPA (8Br + MPA) for an additional 72 h. miR-181 family (A), FOXO1A (B), PRL (C), IGFBP1 (D), DCN (E), and TIMP3 (F) mRNA expression levels were examined by qRT-PCR. [score:9]
miR-181a inhibitor specifically suppressed endogenous miR-181a expression without affecting miR-181b, miR-181c, or miR-181d levels in hESC (Figure  2A). [score:7]
Various potential miR-181 family targets, such as ETS1, CREB1/3, Esr1, and PGR, are involved during differentiation and decidualization events [16- 18]. [score:3]
MicroRNA-181a (miR-181a), which belongs to the miR-181 family, is a key modulator of cellular differentiation. [score:1]
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30
[+] score: 20
Auxiliary pairing regulates miRNA–target specificity in vivoAs a striking indication that auxiliary pairing regulates miRNA–target specificity, duplex structure analysis revealed distinct binding patterns for members of miRNA seed families (for example, let-7, miR-30, miR-181 and miR-125) (Fig. 4d). [score:7]
identified functional, non-canonical regulation globally for miR-128 and miR-124 (Fig. 2), and for individual miR-9, miR-181, miR-30 and miR-125 targets (Fig. 4f and Fig. 8b–m). [score:4]
As a striking indication that auxiliary pairing regulates miRNA–target specificity, duplex structure analysis revealed distinct binding patterns for members of miRNA seed families (for example, let-7, miR-30, miR-181 and miR-125) (Fig. 4d). [score:4]
Analysis of miR-125 and miR-181 families revealed additional intra -family target preferences (Supplementary Fig. 9a–d). [score:3]
Similarly, miR-181 family members were enriched in both seed -dependent and -independent classes. [score:1]
Interestingly, a number of major miRNAs enriched for seedless interactions (for example, miR-9, miR-181, miR-30 and miR-186) have AU-rich seed sites, indicating that weak seed-pairing stability may favour seedless non-canonical interactions 10. [score:1]
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31
[+] score: 19
Besides miRNA 181a, miR-220b, miR-513a-3p, miR-181b, miR-181c, miR-181d, miR-548n and miR-127-5p, are also predicted to target and regulate the expression of OPN. [score:6]
OA patients have higher expression of miR-220b, miR-513a-3p and miR-548n, but lower expression of miR-181a, miR-181b, miR-181c, miR-181d and miR-127-5p, compared to non-OA patients (Fig. 1A). [score:4]
As OPN increased in the pathogenesis of OA 32, we focused on the down-expressed miRNA, including miR-181a, miR-181b, miR-181c, miR-181d and miR-127-5p. [score:3]
In total, eight potential regulatory miRNAs, including miR-220b, miR-513a-3p, miR-181a, miR-181b, miR-181c, miR-181d, miR-548n and miR-127-5p, were identified by the five algorithms. [score:2]
This compelling study is indicating miR181 family members have critical importance in the establishment and development of OA. [score:2]
miR-miR181 family members have been reported to regulate the differentiation stages of chondrocyte and chondrocyte formation 40. [score:2]
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32
[+] score: 18
Together, these results demonstrate that a 400-bp region of the GARP 3’ UTR, that is directly targeted by miR-142-3p, miR-185 and the four miR-181, controls GARP protein levels and the amounts of TGF-β1 that are processed and secreted by human CD4 [+] T cells. [score:4]
Mutation of the miR-142-3p binding site, but not that of the miR-181 site, suppressed the ability of the miR-142-3p mimic to decrease reporter activity in 293 cells (Figure 6D). [score:4]
Conversely, mutation of the miR-181 site, but not that of the miR-142-3p site, suppressed the ability of the four m iR-181 family members to decrease reporter activity (Figure 6D). [score:4]
Finally, miR-185 and miR-181c were expressed at lower levels, and 2.9 to 5.7 times more in Th than in Treg clones. [score:3]
Others have reported a reduced expression of miR-142-3p and miR-181 b and d in murine or human Tregs by comparison to Th cells [37, 38, 44, 46]. [score:3]
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33
[+] score: 18
During myogenesis it is up-regulated by SRFs and MEF2, and in a self-regulatory manner, it suppresses YY1 and HDAC4 translation by targeting their 3′-UTRs [48, 49]; miR-146a is another positive regulator of myogenesis, since it modulates the activity of NUMB protein, which promotes satellite cell differentiation towards muscle cells by inhibiting Notch signaling [55, 56]; miR-181 is involved in skeletal muscle differentiation and regeneration after injury and one of its targets is Hox-A11, which in turn represses transcription of MyoD [54]; miR-214 was identified in zebrafish as regulating the muscle development. [score:18]
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[+] score: 17
Interestingly, mutation of the miR181 site also decreased of luciferase in pMirTarget 3′ UTR hGRβ, but this was not observed in the UMUC-3. Total RNA was extracted from the UMUC-3 and T24 cells to measure the miRNA expression that may target the 3′ UTR of human GRβ (Figure 5C). [score:6]
Dex treatment decreased expression of miR144, miR181a, and miR181c in the T24 cells, but not in the UMUC-3 cells (Figure 6B). [score:3]
Insulin did not significantly change expression of miR33a, miR144, miR181a, miR181b, miR181c, or miR181d in the T24 cells. [score:3]
Next, we wanted to determine if miR33a, miR144, miR181a, miR181b, miR181c, or miR181d changed during a scratch assay and if this affected the human GRβ or GRα expression. [score:2]
Interestingly, miR33a, miR144, miR181a, miR181b, miR181c, and miR181d were all increased in the T24 cells. [score:1]
The T24 and UMUC-3 bladder cancer cells were transfected with the 3′UTR GRβ-Luc expression construct with mutation in the miRNA binding site for miR181, miR144, or miR33a and was measured by a luciferase assay, and normalized to renilla (B). [score:1]
Three miRNAs were predicted to bind the 3′UTR of human GRβ (miR33a, miR181-a/b/c/d, and miR144). [score:1]
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35
[+] score: 17
The striking up-regulation of all the members of the miR-181 family upon lt-NES cell differentiation (Figure 1E right panel) points to potential roles of these miRNAs in human neuronal lineage. [score:4]
Expression of miR-181 family members can be detected in a variety of tissues, with the highest levels found in the brain [37]– [39]. [score:3]
Figure S2 Expression of miR-181 family members in hES cells, lt-NES cells and derived differentiating cultures. [score:3]
The other members of the miR-181 family showed comparable expression patterns (Figure S2). [score:3]
Northern blot analyses showing expression of mature miR-181b, miR-181c and miR-181d in human ES cells (ES), lt-NES cells (NES) and lt-NES cells differentiated for 15 days (ND15) and 30 days (ND30) from the I3 and H9.2 cell lines. [score:3]
Among these, we found miR-153, miR-324-5p/3p and the miR-181 family (Figure 1E right panel), for which evidence from other studies points to potential roles in the nervous system. [score:1]
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36
[+] score: 17
Similarly, major product, miR-181 was strongly up-regulated during RA treatment while the minor product, miR-181* was not detected in any cell type. [score:4]
Similarly, miR-181 family members, which are located in three genomic clusters: mir-181a-1 and mir-181b-1 on chromosome 1; mir-181a-2 and mir-181b-2 on chromosome 9; and mir-181c and mir-181d on chromosome 19, were all up-regulated during the RA time-course, but miR-181a* and miR-181d had log2 intensity below threshold at 28 days RA (Fig. 3B). [score:4]
The expression levels of the same miR-302 (A; bottom left panel) and miR-181 (B; bottom right panel) genomic clusters in NT2-undiff and NT2-28D plotted as yellow and blue bars, respectively. [score:3]
The expression levels of the members of the miR-302 (A) and the miR-181 (B) genomic clusters during neural differentiation plotted as heatmaps (top panels). [score:3]
0011109.g003 Figure 3The expression levels of the members of the miR-302 (A) and the miR-181 (B) genomic clusters during neural differentiation plotted as heatmaps (top panels). [score:3]
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37
[+] score: 17
For example, miR-181 upregulates expression of let-7 by effectively repressing Lin28 expression, and eventually promoting megakaryocytic differentiation, thus providing insight into future development of miRNA-oriented therapeutics [33]. [score:9]
It has been reported that Lin28 mRNA expression can be depressed by several other miRNAs including miR-125, miR-9, and miR-30 [39] and miR-181 [33], and Lin28 expression can be modulated by proteasome inhibitors such as MG132 [40]. [score:7]
Li X. Zhang J. Gao L. McClellan S. Finan M. A. Butler T. W. Owen L. B. Piazza G. A. Xi Y. MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit Cell Death Differ. [score:1]
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38
[+] score: 16
Value Targets INTERACTION EFFECT miR-205 +2.44 CDH1, ZEB1/2, ERRB3, AKTCarraway et al., 1997 miR-155 +1.90 Inhibits negative regulators of inflammation (SHIP1, SOCS)Elton et al., 2013 miR-10b +1.48 HOXA1 and NFKBFang et al., 2010; Tonja, 2012 miR-31 +1.38 ICAM1, E-SelectinSuárez et al., 2010 miR-181 −1.60 Zeb2, MCL1, BCL2L11, BCL2,PTEN, DUSP6, PTPN11Pati et al., 2014 miR-17 −1.83 APP, TGFBRII, SMAD2, SMAD4, p21, BIM (BCL2L11), PTEN. [score:6]
In fact, miR-181 is induced by LIF, a cytokine which inhibits the proliferation of stem cells, and hence, it inhibits neurogenesis (Pati et al., 2014). [score:5]
One of the target of miR-181 is MCL1, which however, has two isoforms: while the isoform 1 is anti-apoptotic, the isoform 2 is pro-apoptotic. [score:3]
The evaluation of miR-181 effects according to its targets, suggests that Older Men Group could have higher levels than Older Women Group of the following activities: more cell adhesion (i. e., more CdhE due to low ZEB2), viability (more PI3K/AKT due to low PTEN), more MAPK signaling (i. e., potentially more ERK [*], JUN [*], p38 [*]), more pro-apoptotic activity (less Bcl2), and low cytoskeleton organization (less RhoA activation due to the loss of PTPN11 effect on Rock2). [score:1]
The negative super-ratio observed with miR-181 (interaction = −1.60) is also consistent with the miR-17 finding. [score:1]
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39
[+] score: 15
miR-221 was strongly upregulated, whereas miR-128, miR-181a, miR-181b and miR-181c were downregulated in glioblastoma [29]. [score:7]
Pekarsky et al. discovered that the expression levels of miR-29 and miR-181 were inversely correlated with Tcl1 expression in CLL. [score:5]
Their results showed that miR-29 and miR-181 might be candidates for therapeutic agents in CLL overexpressing Tcl1 [30]. [score:3]
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40
[+] score: 15
For example, miR-181 and miR-153 promote apoptosis by directly targeting B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) mRNA and repressing its translation, thereby inhibiting gliomagenesis [84]. [score:8]
Moreover, miR-181 downregulation is more prominent in grade III and IV glioma than that in lower grades [84, 87]. [score:4]
Both miR-181 and miR-153 expression is decreased in glioma cell lines and a subset of clinical glioma specimens, suggesting roles of the two miRNAs in glioma progression. [score:3]
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41
[+] score: 14
For example, the expressions of miR-181c and -181d were decreased after inhibiting β-catenin activity, confirming the positive correlation of miR-181 family members’ expression and β-catenin [43]. [score:7]
In contrast, expression levels of miR-181 family members, including miR-181d, were significantly reduced after blocking the activity of β-catenin, suggesting that miR-181d might antagonize the effects of β-catenin inhibition, thereby inducing drug resistance. [score:5]
Five miRNAs–miR-181c, -181d, -186, -30b and -30d–were found to regulate this pathway; except for miR-30b, all of these occurred in more than one condition. [score:2]
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42
[+] score: 14
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-17, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-30a, hsa-mir-93, hsa-mir-96, hsa-mir-99a, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-105-1, hsa-mir-105-2, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-205, hsa-mir-212, hsa-mir-181a-1, hsa-mir-222, hsa-mir-224, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-132, hsa-mir-141, hsa-mir-145, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-146a, hsa-mir-150, hsa-mir-184, hsa-mir-188, hsa-mir-320a, hsa-mir-181b-2, hsa-mir-30c-1, hsa-mir-302a, hsa-mir-34c, hsa-mir-30e, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-371a, hsa-mir-372, hsa-mir-376a-1, hsa-mir-378a, hsa-mir-383, hsa-mir-339, hsa-mir-133b, hsa-mir-345, hsa-mir-425, hsa-mir-483, hsa-mir-146b, hsa-mir-202, hsa-mir-193b, hsa-mir-181d, hsa-mir-498, hsa-mir-518f, hsa-mir-518b, hsa-mir-520c, hsa-mir-518c, hsa-mir-518e, hsa-mir-518a-1, hsa-mir-518d, hsa-mir-518a-2, hsa-mir-503, hsa-mir-513a-1, hsa-mir-513a-2, hsa-mir-376a-2, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-645, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-744, 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-302e, hsa-mir-302f, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-548q, hsa-mir-548s, hsa-mir-378b, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-320e, hsa-mir-548x, hsa-mir-378c, 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-371b, 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
With the mouse mo del, it has been shown that a minimal uterine expression of miR-181 is essential for the onset of embryo implantation and that it is regulated by the leukemia inhibitory factor (LIF) [80]. [score:6]
Also miRNA precursors are present in human sperm, such as pri-miR-181, whose targets might have a function in early embryonic development and globally decrease at the 4–8-cell stage of human embryo development [8]. [score:5]
A specific target of pri-miRNA-181 is the embryonic stem cell pluripotency factor, termed coactivator -associated arginine methyltransferase I (CARM1). [score:3]
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43
[+] score: 14
After determining the expression levels of these miRNAs in the same 7 pairs of NSCLC tissues and normal adjacent tissues, we observed that 8 miRNAs (miR-203, miR-30, let-7, miR-132, miR-181, miR-212, miR-101 and miR-9) were downregulated in the NSCLC tissues, while the other 5 miRNAs (miR-125, miR-98, miR-196, miR-23 and miR-499) were upregulated (Fig. S1). [score:9]
In addition to let-7, miR-181 26, miR-30 29, miR-9 27 28, miR-132 32 33, miR-101 30 and miR-212 31 have also been shown to directly bind the 3′-UTR of LIN28B and repress the translation of this protein. [score:4]
A total of 13 miRNAs, including miR-203, miR-30, let-7, miR-132, miR-181, miR-212, miR-101, miR-9, miR-125, miR-98, miR-196, miR-23 and miR-499, were identified as candidate miRNAs by all three computational algorithms (Table S2). [score:1]
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44
[+] score: 14
miRNAs (e. g. miR-146a[49], miR-34[50], miR-181[51]) that downregulate protective genes against AD (e. g., complement factor H)/upregulate “pro-AD” genes (e. g. p53, SIRT1)/are correlated with amount of Aβ plaque and NFTs, exhibit upregulated in the brain and/or peripheral circulation of AD patients. [score:10]
Addition of Aβ peptides to primary neuronal cell cultures/primary human astrocytes cultures has been shown to downregulate miR-9/miR-181[51]. [score:4]
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45
[+] score: 14
All the isoforms and combined sum of expression of isoforms showed the same pattern in plots created using our tool as shown in the paper, with poor overall survival observed in the group having low expression of miR-181 isoforms. [score:5]
In another study, Chen et al [61], have demonstrated down-regulation of several isoforms of miR-181 (miR-181-a, miR-181-b, miR-181-c and miR-181-d) being correlated with poor overall survival in acute myeloid leukemia (AML). [score:4]
Prognostic plot for sum of expression of hsa-mir-181 isoforms a,b,c and d in TCGA AML data. [score:3]
Additional file 1: Figures S1-S4 provided in supplementary data show prognostic plots for miR-181 isoforms in AML data. [score:1]
Prognostic plot created using PROGmiR for isoforms a, b, c and d of miRNA hsa-miR-181 identified as prognostically important biomarker in Acute Myeloid Leukemia (AML) by Chen et al, using TCGA data. [score:1]
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46
[+] score: 14
Significantly, the upregulated miRNAs are enriched in miR-199a cluster (P = 1.49 × 10 [-4]), whereas the downregulated miRNAs are enriched in miR-181c cluster (P = 2.71 × 10 [-3]). [score:7]
For the miRNA family, the upregulated miRNAs and downregulated miRNAs are enriched in miR-17 family (P = 4.03 × 10 [-3]) and miR-181 family (P = 1.64 × 10 [-3]), respectively. [score:7]
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47
[+] score: 14
Suppression of miR-181-a/-b produced a significant delay in tumour development in a mouse mo del of MM, confirming that this miRNA nourishes MM tumour growth. [score:4]
Pichiorri et al. [25] have shown that miR-181-a/-b, miR-106b~25 and miR-32 are up-regulated in MGUS, MM primary cells and cell lines. [score:4]
Moreover, miR-21, as well as miR-181-a/-b, is upregulated in two drug resistant MM cell lines when compared with parental line [31]. [score:3]
Finally, miR-181-a/-b were significantly upregulated in two drug resistant MM cell lines when compared with parental line [31]. [score:3]
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48
[+] score: 13
Upregulated miR-181 in CRC cases might also influence gene expression level of the Bcl-2 family members [50]. [score:6]
Furthermore, miR-21* (predicted for BCL2, MAL, SFRP1, SOCS3, PTGS2), miR-181c (predicted for ALDH1A3, BCL2, MAL), and let-7i* (predicted for BCL2, CYP27B1, and SOCS3) were also found to be upregulated in AD and CRC samples (Fig.   4). [score:4]
Fig. 4 Normalised Ct values of selected miRNAs (hsa-miR-21, hsa-miR-21*, hsa-miR-181c, hsa-let-7i*) targeting the selected marker set. [score:3]
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49
[+] score: 13
miR-138 is upregulated in glioma cells with acquired TMZ resistance and in recurrent glioblastomas in vivoMicroarray -based miRNA expression profiling of parental and TMZ-resistant (TMZR) LN-18, LN-229 and LN-308 cells revealed several differentially expressed MiRNAs (Figure 1A), including several miRNAs previously implicated in TMZ resistance, such as mir-125b [10], miR-181 [12] or miR-221/222 [13]. [score:8]
Microarray -based miRNA expression profiling of parental and TMZ-resistant (TMZR) LN-18, LN-229 and LN-308 cells revealed several differentially expressed MiRNAs (Figure 1A), including several miRNAs previously implicated in TMZ resistance, such as mir-125b [10], miR-181 [12] or miR-221/222 [13]. [score:5]
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50
[+] score: 13
As a critical regulator of tumor cell migration and invasion and breast cancer progression in vitro, miR-181 could potentially be an important therapeutic target [243]. [score:4]
We and others have demonstrated the mir-181 family of microRNAs to be up-regulated by TGF β and activin, a closely related TGF β family member [243, 247, 249]. [score:4]
In hepatocellular carcinoma, TGF β -induced miR-181 targets TIMP3 for degradation, thereby increasing invasiveness of the cells [247]. [score:3]
We also found miR-181 to be a downstream regulator of activin/TGF β -induced cellular migration and invasion in breast cancer (Figure 4). [score:2]
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51
[+] score: 12
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-18a, hsa-mir-19a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-96, hsa-mir-99a, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-192, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-139, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-183, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-210, hsa-mir-181a-1, hsa-mir-214, hsa-mir-215, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-130a, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-140, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-153-1, hsa-mir-153-2, hsa-mir-191, 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-185, hsa-mir-190a, hsa-mir-194-1, hsa-mir-195, hsa-mir-206, hsa-mir-200c, hsa-mir-155, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-101-2, hsa-mir-219a-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-99b, hsa-mir-296, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-370, hsa-mir-373, hsa-mir-374a, hsa-mir-375, hsa-mir-376a-1, hsa-mir-151a, hsa-mir-148b, hsa-mir-331, hsa-mir-338, hsa-mir-335, hsa-mir-423, hsa-mir-18b, hsa-mir-20b, hsa-mir-429, hsa-mir-491, hsa-mir-146b, hsa-mir-193b, hsa-mir-181d, hsa-mir-517a, hsa-mir-500a, hsa-mir-376a-2, hsa-mir-92b, hsa-mir-33b, hsa-mir-637, hsa-mir-151b, hsa-mir-298, hsa-mir-190b, hsa-mir-374b, hsa-mir-500b, hsa-mir-374c, hsa-mir-219b, hsa-mir-203b
Polycyclic aromatic hydrocarbon (PAH) -mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK. [score:7]
Zhang and Pan (2009) have evaluated the effects of Hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine (also known as hexogen or cyclonite) (RDX) on miRNA expression in mouse brain and liver, most of the miRNAs that showed altered expression, including let-7, miR-17-92, miR-10b, miR-15, miR-16, miR-26, and miR-181, were related to toxicant-metabolizing enzymes, and genes related to carcinogenesis, and neurotoxicity, in addition, consistent with the known neurotoxic effects of RDX, the authors documented significant changes in miRNA expression in the brains of RDX -treated animals, such as miR-206, miR-30a, miR-30c, miR-30d, and miR-195. [score:5]
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52
[+] score: 12
miRNAs observed to be part of the positive feedback loops, hsa-miR-21-5p, hsa-miR-181c-5p, hsa-let-7c-5p, hsa-let-7b-3p and hsa-miR-155-5p, target the negative regulators of the NFAT, thus facilitating NFAT activation (Figure 3). [score:4]
The second miRNA target of CSNK1A1, hsa-miR-181c, however, has not been studied in detail for its function in T cell activation and immune responses. [score:3]
hsa-miR-181c is part of the miR-181 family, consisting of miR-181a, miR-181b and miR-181c. [score:1]
Out of the 11 miRNAs, six (hsa-miR-21-3p, hsa-let-7b-5p, hsa-miR-17-5p, hsa-miR-19a-3p, hsa-miR-92b-3p and hsa-miR-17-3p) are involved in a negative feedback loops that modulates NFAT activity down and five miRNAs (hsa-miR-21-5p, hsa-miR-181c-5p, hsa-let-7c-5p, hsa-let-7b-3p and hsa-miR-155-5p) are involved in a positive feedback loops facilitating NFAT activation. [score:1]
Kishore et al., using the cross-linking and immunoprecipitation (CLIP) method, have validated the interaction between CSNK1A1 and hsa-miR-181c [86]. [score:1]
In the present study, hsa-miR-181c has been described to be potentially involved in a positive feedback loop to activate the calcineurin/NFAT pathway by silencing the negative of the pathway, CSNK1A1. [score:1]
These data thus suggest a potential role of hsa-miR-181c in silencing CSNK1A1, which would activate the NFAT pathway and immune response. [score:1]
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53
[+] score: 12
Tumor suppressor miRNAs (miR-15b, miR-16, miR-34, miR-181b, miR-181c, and miR-497) target anti-apoptotic Bcl-2. These miRNA clusters are downregulated in gastric cancer cells, leading to increased expression of Bcl-2 and inhibition of apoptosis. [score:12]
[1 to 20 of 1 sentences]
54
[+] score: 11
The miR-181 family has been shown to exert oncogenic effects via suppression of the apoptosis gene Bcl-2. Therefore, the sequestration of miR-181a by MEG3 results in upregulation of Bcl-2, and suppresses gastric carcinogenesis [22]. [score:8]
LncRNA MEG3 was also found to be capable of inhibiting gastric cancer cell proliferation, migration, and invasion by competitively binding with members of the miR-181 family such as MEG3 sequestering oncogenic miR-181a (Table 1 and Figure 1). [score:3]
[1 to 20 of 2 sentences]
55
[+] score: 11
The overlap between human AD and our in vitro and in vivo AD mo dels indicates that amongst the complex pathology in human AD brain, down-regulation of miR-9, miR-181c, miR-30c, miR-20b, miR-148b and Let-7i could be attributed at least in part to the presence of Aβ. [score:4]
Three of the down-regulated miRNAs (miR-181, miR-21 and Let-7) have this pathway as their top candidate with p-values of less than 0.001. [score:4]
Individual TaqMan assays (Applied Biosystems) were used to analyse the expression of the following mature mouse miRNAs: miR-181c, miR-9, miR-20b, miR-21, miR-30c, miR-148b, miR-361, miR-409-3p and Let-7i. [score:2]
In comparison, miR-21, miR-181 and Let-7 have well characterized roles in cancer and it is not surprising therefore that their target genes result in enrichment for cancer-related pathways as well. [score:1]
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56
[+] score: 11
For instance, several brain-enriched miRNAs, miR-128, miR-181a, miR-181b, and miR-181c, are mainly down-regulated in glioblastomas [7], whereas miR-221 and miR-21 are strongly up-regulated in GBM and grade II–IV astrocytic tumors [8]. [score:7]
Generally, microRNAs are mainly down-regulated in cancers, as is the case with miR-128, miR-181a, miR-181b, and miR-181c in glioblastomas [7]. [score:4]
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57
[+] score: 11
A primary regulator of exercise -induced SIRT1 expression is NAD [+] availability through AMPK (White and Schenk, 2012) and it seems plausible that AMPK, rather than miR-133b or miR-181, may be the primary regulator of post-exercise changes in SIRT1 expression. [score:7]
The expression of miR-181 increased at 4 h post-exercise with PRO (~80%, P < 0.05) that resulted in higher miR-181 with PRO compared to PLA at 4 h (~76%, P < 0.05; Figure 2A). [score:2]
We also found greater miR-133b and miR-181 abundance with post-exercise protein ingestion. [score:1]
Figure 2(A) mir-181-5p, (B) miR-378-5p, (C) miR-486-5p, and (D) miR-494-3p abundance at rest and at 4 h post-exercise recovery following a concurrent exercise session of resistance (8 sets of 5 leg extension at 80% 1-RM) and endurance (30 min cycling at 70% VO [2peak]) exercise and ingestion of either 500-mL PLA or PRO beverage immediately after exercise. [score:1]
[1 to 20 of 4 sentences]
58
[+] score: 10
In order to over-express miRNAs in differentiating ESCs, six synthetic mature miRNAs (Invitrogen), mir-181c/338-5p/222/196a/196b/let-7e, were pooled together equivalently. [score:3]
Six synthetic mature miRNA inhibitors including mir-181c/338-5p/222/196a/196b/let-7e were pooled together equivalently. [score:3]
We over-expressed a pool of miRNAs consisting mir-181c/338-5p/222/196a/196b/let-7e at 3 days of differentiated ES cells and then examined the DE markers 2 days later. [score:3]
Red: mir-338-5p binding site; Yellow: mir-181c binding site; Blue: mir-196 a/mir-196b binding site. [score:1]
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59
[+] score: 10
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-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-98, hsa-mir-99a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-181a-1, hsa-mir-221, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-27b, hsa-mir-30b, hsa-mir-130a, hsa-mir-152, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-185, hsa-mir-193a, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-181b-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-99b, hsa-mir-130b, hsa-mir-30e, hsa-mir-363, hsa-mir-374a, hsa-mir-375, hsa-mir-378a, hsa-mir-148b, hsa-mir-331, hsa-mir-339, hsa-mir-423, hsa-mir-20b, hsa-mir-491, hsa-mir-193b, hsa-mir-181d, hsa-mir-92b, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, bta-mir-29a, bta-let-7f-2, bta-mir-148a, bta-mir-18a, bta-mir-20a, bta-mir-221, bta-mir-27a, bta-mir-30d, bta-mir-320a-2, bta-mir-99a, bta-mir-181a-2, bta-mir-27b, bta-mir-30b, bta-mir-106a, bta-mir-10a, bta-mir-15b, bta-mir-181b-2, bta-mir-193a, bta-mir-20b, bta-mir-30e, bta-mir-92a-2, bta-mir-98, bta-let-7d, bta-mir-148b, bta-mir-17, bta-mir-181c, bta-mir-191, bta-mir-200c, bta-mir-22, bta-mir-29b-2, bta-mir-29c, bta-mir-423, bta-let-7g, bta-mir-10b, bta-mir-24-2, bta-mir-30a, bta-let-7a-1, bta-let-7f-1, bta-mir-30c, bta-let-7i, bta-mir-25, bta-mir-363, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, bta-mir-15a, bta-mir-19a, bta-mir-19b, bta-mir-331, bta-mir-374a, bta-mir-99b, hsa-mir-374b, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, bta-mir-1-2, bta-mir-1-1, bta-mir-130a, bta-mir-130b, bta-mir-152, bta-mir-181d, bta-mir-182, bta-mir-185, bta-mir-24-1, bta-mir-193b, bta-mir-29d, bta-mir-30f, bta-mir-339a, bta-mir-374b, bta-mir-375, bta-mir-378-1, bta-mir-491, bta-mir-92a-1, bta-mir-92b, bta-mir-9-1, bta-mir-9-2, bta-mir-29e, bta-mir-29b-1, bta-mir-181a-1, bta-mir-181b-1, bta-mir-320b, bta-mir-339b, bta-mir-19b-2, bta-mir-320a-1, bta-mir-193a-2, bta-mir-378-2, hsa-mir-378b, hsa-mir-320e, hsa-mir-378c, bta-mir-148c, hsa-mir-374c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-378j, bta-mir-378b, bta-mir-378c, bta-mir-378d, bta-mir-374c, bta-mir-148d
It was reported that miR-181c/d can inhibit cell cycle and proliferation and that miR-181c regulates TNF-α[65]. [score:4]
The miR-181 (181a/b/c/d) family is related to the development of different cells. [score:2]
Among all miRNAs clusters, there were several pre-miRNAs with intervening sequences of less than 1 kb, including 10 known clusters (miR-99b/let-7e/125a, miR-24-2/27b/23b, miR-99a/let-7c, miR-29b/29a, miR-221/222, miR-98/let-7f, miR-181c/d, miR-363/92a/19b-2/106a, miR-363/92a/19b-2, miR-181b-1/181a-1 and miR-17/18a/19b-1/92a-1) and 4 novel miRNAs clusters (cluster 3, 9, 12, 22). [score:1]
In the miR-181 family, miR-181a and miR-181b were dominant types with 13,345 reads and 3,333 reads, respectively. [score:1]
The let-7 family had 9 members, miR-181 family had 4 members (miR-181a/b/c/d) and miR-30 family had 5 members (miR-30a/b/c/d/e). [score:1]
In our study, 8 miRNA families (let-7, mir-1, mir-17, mir-181, mir-148, mir-30, mir-92 and mir-99) were found with at least 3 members among all exosome miRNAs. [score:1]
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60
[+] score: 10
Interestingly, miR-181c has been implicated as a potential MS biomarker and is downregulated in the cerebrospinal fluid (CSF) of MS patients (Haghikia et al., 2012). [score:4]
Inhibition of miRNA-181 reduces forebrain ischemia -induced neuronal loss. [score:3]
Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. [score:1]
miRNAs within the miR-181 family have been identified as miRNAs with possible roles in OL biology. [score:1]
The miR-181 family has previously been implicated in CNS ischemia and inflammation (Hutchison et al., 2013; Moon et al., 2013), although a functional role for this miRNA in OL differentiation has not yet been established. [score:1]
[1 to 20 of 5 sentences]
61
[+] score: 10
miR-181a, miR-181c and miR-181d were downregulated in two normal aging mouse mo dels, C57BL/6J and CBA/J [82], implying that aging can lead to decreased levels of miR-181, which then inhibits proliferation. [score:6]
MiR-181 is known to cause proliferation of hair cells in the chicken inner ear and inhibition of miR-181a reduces proliferation [85]. [score:3]
This suggests that during the early post-natal growth of the inner ear, miR-181 is required, but may not be necessary during the adult stage. [score:1]
[1 to 20 of 3 sentences]
62
[+] score: 9
Since miR-181b-abundant glioma cells is more sensitive to temozolomide (TMZ) [21], aplysin enhances TMZ action through increasing the expression of miR-181 in TMZ-resistant glioma cells, which results in MEK1 (mitogen-activated protein kinase kinase 1) downregulation [22]. [score:6]
For example, miR-181 is related to TMZ-resistance of glioma, and interestingly, aplysin can also enhance the sensitivity of glioma cells to TMZ. [score:1]
For example, in human pancreatic cancer cells treated with circumin, miR-181d is significantly changed, but miR-181c (chr19:13874699-13874808), which is close to miR-181d (chr19:13874875-13875011) in the genome, is not changed [48]. [score:1]
Thus, researchers investigated their association and found aplysin exerts its function through increasing the expression of miR-181. [score:1]
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63
[+] score: 9
Consistently, we previously demonstrated that CBX7 negatively regulates the expression of miR-181 that has among its targets CBX7, creating a synergistic loop that contributes to breast cancer progression [11]. [score:6]
The results presented in Fig.   1 confirm a drastic overexpression of miR-181, miR-137, miR-199, miR-706 and miR-719 and repression of miR-155 in Cbx7 KO MEFs in comparison with the WT ones. [score:3]
[1 to 20 of 2 sentences]
64
[+] score: 9
Although in most instances miR-181a-1 attenuates inflammatory responses, in some cases miR-181 family members are upregulated by inflammatory signals and have been reported to be pro-inflammatory, which may explain its reported dual roles as a tumor suppressor-miR or onco-miR in different types of cancers. [score:6]
It should also be noted that miR-181 is an important regulator of hematopoiesis, therefore, decreased miR-181a-1 may impact hematopoietic lineage development during aging [36]. [score:3]
[1 to 20 of 2 sentences]
65
[+] score: 9
Indeed, miRNA inhibitors were designed to inhibit individual members of miRNA families, and, for example, miR-181, a miRNA essential for differentiation [15] was below the threshold of detection in this screen, likely due to the high redundancy of the miR-181 family. [score:5]
The positive control was a miR-181 LNA inhibiting the whole miR-181family (Exiqon) and the negative controls were a mutant of this oligonucleotide ([15] or mock transfected cells. [score:3]
Thus, a few miRNAs, miR-133, miR-1, miR-206, miR-181 and miR-27a, have previously been shown to be important in skeletal muscle cell terminal differentiation [5]. [score:1]
[1 to 20 of 3 sentences]
66
[+] score: 9
MicroRNAs that function as oncogenes, including miR-17, miR-21, and miR-106a, were upregulated, whereas microRNAs that function as tumor suppressors, such as miR-101, miR-181, miR-449, miR-486, and let-7a, were downregulated in gastric cancer [42, 43]. [score:9]
[1 to 20 of 1 sentences]
67
[+] score: 9
Interestingly, human neutrophils only express miR-181d and not miR-181c of the miR-181c cluster (Figure 3h). [score:3]
Expression levels are shown for the following clusters: A) miR-17-92, B) miR-106b-25, C) miR-23a-27a-24, D) miR-16-1 and miR-15b, E) let-7a-1 and let-7a-3, F) miR-29a and miR-29c, G) miR-181a and H) miR-181c. [score:3]
We also found that neutrophils expressed both members of the miR-181a cluster but only miR-181d of the miR-181c cluster. [score:3]
[1 to 20 of 3 sentences]
68
[+] score: 9
Accordingly, circulating levels of miR-181 have been suggested to be a potential biomarker of non-alcoholic fatty liver disease [124], and have been found to be decreased in monocytes of obese subjects, although weight loss normalized its expression [125]. [score:5]
Figueredo et al. have recently demonstrated daily variation in miR-16 and miR-181 expression in human leukocytes, both microRNAs peaked between 8:00 a. m. and 16:00 p. m. [121]. [score:3]
miR-181 has been associated with glioblastoma [122] and it has been proposed to be a modulator of the lipid droplet content in human hepatic cells [123], suggesting a link with lipid metabolism. [score:1]
[1 to 20 of 3 sentences]
69
[+] score: 9
The expression of miR-181c, miR-212 and miR-512 was silenced with DNA hypermethylation in gastric cancer, and their restored expression could induce decreased gastric cancer cell growth via inhibition of oncogenes expression (Refs 81, 82, 83). [score:9]
[1 to 20 of 1 sentences]
70
[+] score: 9
In hematopoietic stem cells, miR-181a-2*, a member of the miR-181 family and deregulated in both 2102Ep and NTera-2 cells, can directly target NANOG [101]. [score:5]
The expression of the miR-181 family increases during early hESC differentiation and has previously been identified as regulators of stem cell differentiation, including that of hESCs and CSCs [102– 105]. [score:4]
[1 to 20 of 2 sentences]
71
[+] score: 9
Of the most up-expressed miRNA (miRNA-181a-3p) in HepG2/DOX, one target gene RBM22 supported by three softwares (Mireap, miRDB and PicTar), was expected to be the common targets of seven other significantly differentially expressed miRNAs including miR-21, miR-101, miR-217, miR-590-5p, miR-181b, miR-181c, and miR-181d. [score:9]
[1 to 20 of 1 sentences]
72
[+] score: 9
miR-181 downregulation enhanced by ~ 60% ALX/FPR2 protein expression in CFBE41o-cells (Fig.   2D), although it did not change ALX/FPR2 mRNA expression (results not shown). [score:8]
Along these lines, the downstream signaling leading to the enhanced LXA [4] -induced phagocytic activity, observed when miR-181 was inhibited, requires further investigation. [score:1]
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73
[+] score: 9
miR-1236 was a negative regulator of VEGFR-3 in lymphangiogenesis [28] and miR-181 was found to be an important regulator of angiogenesis and lymphangiogenesis via Prox-1 inhibition [29]. [score:5]
Prox1 expression is negatively regulated by miR-181 in endothelial cells. [score:4]
[1 to 20 of 2 sentences]
74
[+] score: 9
Ciafrè et al. [54] demonstrated aberrant expression profiles of numerous miRNAs such as miR-221 which were strongly upregulated in GBM and miRNAs such as miR-128, miR-181a, miR-181b, and miR-181c which were shown to be downregulated in GBM. [score:9]
[1 to 20 of 1 sentences]
75
[+] score: 8
miR-181 expression was also enhanced in SPARC expressed medulloblastoma cells compared to controls. [score:4]
miR-181 expression was shown to enhance radio and chemo sensitivity [61– 63]. [score:3]
Taken together, these findings support the hypothesis that mir-181 may be involved in enhancing radio response in medulloblastoma. [score:1]
[1 to 20 of 3 sentences]
76
[+] score: 8
This approach enabled the identification of miRNAs whose expression is significantly altered in tumors compared with peripheral brain areas from the same patient, including miR-221, strongly up-regulated in GBM, and a set of brain-enriched miRNAs, miR-128, miR-181a, miR-181b, and miR-181c, which were down-regulated in glioblastoma [36]. [score:8]
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77
[+] score: 8
Cluster 2 miRNAs (light blue) overwhelmingly upregulated p27 phosphorylation and cluster 5 miRNAs upregulated S6 phosphorylation consistent with that which was observed for other members of their respective clusters in screen 1. MiR-885-3p, miR208b and miR-181c* regulated the highest number of components within the phosphoprotein network. [score:8]
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78
[+] score: 8
Responses to ischemia in mouse brain also showed increased expression of miR-181 in the core, where cells die, and decreased expression of miR-181 in the penumbra, where cells survive (69). [score:5]
by manipulation of miRNA-related pathways are also found in astrocyte-rich miRNAs, including miR-181 and families, and miR-146a, and their validated targets, GRP78, and Bcl-2 family members (114). [score:3]
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79
[+] score: 8
miR-181 and miR-29 could down-regulate TCL1, Mcl1, Bcl2 and Bcl2L11 [46- 48]. [score:4]
From our analyses, miR-181b appeared to be the strongest TCL1 inhibitor among members of the miR-181 or miR-29 families. [score:3]
Following transfection of miRNA mimics of the miR-181 and miR-29 families, we assessed the TCL1 protein level. [score:1]
[1 to 20 of 3 sentences]
80
[+] score: 8
In particular, CUL3, over expressed in kidney and prostate cancers, is a target of several dysregulated MIRs: MIR22, MIR23A, MIR23B, MIR218-1, MIR218-2, and MIR301, which are down regulated in kidney cancers, and of MIR22, MIR23A, MIR181A, and MIR181C, which are down regulated in prostate cancers (Table 5). [score:8]
[1 to 20 of 1 sentences]
81
[+] score: 8
Based on a miRNA profiling study that identified the miR-17 and miR-181 family members as the most downregulated miRNAs during neutrophil differentiation of NB4 APL cells [52], and our study identifying ULK1 as a novel target of the miR-17 family member miR-106a in lung cancer therapy [53], we hypothesized that this miRNA also targets ULK1 in AML. [score:8]
[1 to 20 of 1 sentences]
82
[+] score: 8
Thus, we inferred that YBX1 and miR-181c was also related to this disease. [score:3]
Although there was no direct evidence pointing out miR-181c associating with breast cancer currently, several studies had demonstrated that miR-181c was implicated in other types cancers [13– 15]. [score:2]
The involvement of miR-181c in the breast cancer was worth concern. [score:1]
There was a cascade named Src → miR-145 → MYC → YBX1 → EGFR → miR-21 → STAT3 → AKT1 → miR-181c with a high score 2.468. [score:1]
Almost all these elements in the cascade were associated with breast cancer except YBX1 and miR-181c. [score:1]
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83
[+] score: 8
Even though miR-181c is possibly co-expressed or repressed with miR-181d, there has not been many research done regarding this co -expression or repression. [score:5]
However, it has been observed that the miR-181 family (miR-181a, miR-181b, miR-181c, and miR-181d), more precisely miR-181c, is activated by HER2 expression [13]. [score:3]
[1 to 20 of 2 sentences]
84
[+] score: 8
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-20a, hsa-mir-21, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-99a, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-16-2, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-204, hsa-mir-205, hsa-mir-181a-1, hsa-mir-216a, hsa-mir-217, hsa-mir-223, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-142, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-146a, hsa-mir-149, hsa-mir-150, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-181b-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-200a, hsa-mir-101-2, hsa-mir-26a-2, hsa-mir-365a, hsa-mir-365b, hsa-mir-370, hsa-mir-375, hsa-mir-378a, hsa-mir-148b, hsa-mir-335, hsa-mir-133b, hsa-mir-451a, hsa-mir-146b, hsa-mir-494, hsa-mir-193b, hsa-mir-181d, hsa-mir-92b, hsa-mir-574, hsa-mir-605, hsa-mir-33b, hsa-mir-378d-2, hsa-mir-216b, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-378b, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-451b, hsa-mir-378j
Pekarsky Y. Santanam U. Cimmino A. Palamarchuk A. Efanov A. Maximov V. Volinia S. Alder H. Liu C. G. Rassenti L. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181 Cancer Res. [score:4]
In particular, miR-181 and miR-155, which are known to regulate B cell differentiation [48, 105, 106], are present in high concentrations in HM [44, 48], suggesting a function in the development of the infant’s immune system. [score:3]
HM is rich in B cell-related microRNAs, such as miR-181 and miR-155, which potentially induce B cell differentiation [108, 110]. [score:1]
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85
[+] score: 8
MiRNA-181 interacts with the 3′ UTR region of the tumor suppressor KLF gene and have ability to inhibit the apoptosis of tumor cells (Zabaleta, 2012). [score:4]
MiRNA-181 targets 3′UTR region of tumor suppressor Krüppel-Like Factor (KLF) encoding gene during Helicobacter pylori infection (Zabaleta, 2012). [score:4]
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86
[+] score: 8
Since we have previously shown that HMGA1 is able to negatively regulate CBX7 expression (Mansueto et al., 2010) and that HMGA1 positively regulates miR-181 that has CBX7 as target, we can envisage a HMGA1-CBX7 network that operates in the regulation of tumour progression and adipocyte cell growth and differentiation. [score:8]
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87
[+] score: 8
Other miRNAs from this paper: hsa-mir-141, hsa-mir-375
Moreover, miR-181c directly repressed MST1 (mammalian STE20-like protein kinase 1), LATS2 (large tumor suppressor 2), MOB1 (MOB kinase activator 1) and SAV1 (Salvador homologue 1), leading to YAP/TAZ activation and subsequent promotion of PC cell survival and chemoresistance both in vitro and in vivo [34]. [score:4]
Noteworthy, emerging data showed that YAP1 is negatively regulated by miR-141 [32], miR-375 [33] and miR-181c [34], which serves an independent prognostic factor for PC patients and functions as tumor suppressors. [score:4]
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88
[+] score: 8
In this respect, there is a long list of predicted miRNAs (i. e. from DIANA-microT, miRanda, TargetScanS algorithms) that may target the 3'UTR of APP, including let-7i, miR-15, -26, -29, -93, -101, -106, and miR-181 which are reportedly down-regulated in AD brain [96, 99]. [score:8]
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89
[+] score: 8
In addition to let-7, the miRNAs miR-26a, miR-181, miR-9, miR-30, miR-125, miR-212 and miR-27 have also been shown to directly bind the 3′UTR of LIN28A/LIN28B and repress translation of the protein, and as these miRNAs are frequently under-expressed in malignant tumors, higher levels of LIN28 expression are seen [31– 34]. [score:8]
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90
[+] score: 7
We verified that coexpression of TCL1 with miR-29 and miR-181 decreased its expression and found inverse correlation between miR-29b, miR-181b, and Tcl1 expression in CLL samples [35]. [score:7]
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91
[+] score: 7
The miRNA signatures generated for ER status (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), for PR status (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and for HER2/ neu status (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) include miRNAs that have previously been identified as dysregulated in breast cancer and other cancers [7, 9, 37- 43] and involved in the regulation of cell functions such as growth, apoptosis, migration and invasion [38, 42, 43]. [score:3]
Notably, two chromosomal locations account for a number of the dysregulated miRNAs in these predictive sets: Ch19q13 (miR-520g, miR-520d, miR-527-528a, miR-520f-520c, miR-181c) and Ch14q32 (miR-342, miR-299, miR-377, miR-376b). [score:2]
Stepwise ANN analysis identified predictive miRNA signatures corresponding with oestrogen (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/ neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. [score:1]
Similarly, four miRNA transcripts (miR-520g, miR-377, miR-527-518a, miR-520f-520c) were identified that predicted tumour PR status with 100% accuracy, and HER2/ neu status was predicted with 100% accuracy by a signature of five miRNAs (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) (Table 3). [score:1]
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92
[+] score: 7
miRNAs of the miR-125 and miR-181 families contribute to the downregulation of Cbx7 during mESC differentiation by directly targeting its 3′UTR [100]. [score:7]
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93
[+] score: 7
Among the up regulated miRNAs in AMLs, a number were already known to be haematopoietic tissue-specific, i. e. miR-142-5p, miR-155, and miR-181 [10], [41], [42], and/or reported highly expressed in a variety of haematological malignancies and solid tumours, i. e. miR-221, and miR-222. [score:4]
MiR-181 regulates the expression of TCL1 (X82240) in CLL [45]. [score:3]
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94
[+] score: 7
microRNAs downregulated in quiescent cells included miR-18, miR-20, miR-29, and miR-7, and microRNAs upregulated with quiescence included let-7b, miR-125a, miR-30, miR-181, miR-26, and miR-199. [score:7]
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95
[+] score: 7
Overexpression of the miR-17-92 cluster and miR-181 enhanced B-cell proliferation, while miR-150 regulated B-cell differentiation (61– 64). [score:4]
When overexpressed, miR-181 has been shown to decrease T-cell numbers (61), but enhance T-cell receptor signaling (65). [score:3]
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96
[+] score: 7
B. Relative expression of miR-181c-3p and miR-30c-5p in plasma of control and CHF patients (n = 45). [score:3]
A. Cell distribution of miR-181c and miR-30c (n = 3), * p < 0.05 vs. [score:1]
It was reported that cardiomyocytes-derived miRNAs (miR-1, miR-208, miR-499, miR-133, miR-30c, miR-181, etc. ) [score:1]
However, results from qRT-PCR suggested that circulating miR-30c and miR-181c level decreased significantly in CHF (Figure 3B and 3C), which is consistent to our profiles data. [score:1]
Figure 3 A. Cell distribution of miR-181c and miR-30c (n = 3), * p < 0.05 vs. [score:1]
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97
[+] score: 7
Moreover, miR-181 targets TIMP3 that is an inhibitor of metalloprotease, inductor of apoptosis and inhibits angiogenesis, cell migration and invasion [174]. [score:7]
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98
[+] score: 7
Interestingly, members of the miR-181 family consistently upregulated the reporter in the Keklikoglou et al. study, while all four members downregulated reporter activity in our study to varying degrees (see Additional file 1, Table S2). [score:7]
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99
[+] score: 7
Similarly, downregulation of miR-181 was responsible for resistance to imatinib by directly targeting the Bcl-2 family member Mcl-1 in chronic myelogenous leukemia cells [16]. [score:7]
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100
[+] score: 7
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-17, hsa-mir-21, hsa-mir-29a, hsa-mir-96, mmu-let-7g, mmu-let-7i, mmu-mir-124-3, mmu-mir-140, mmu-mir-181a-2, mmu-mir-182, mmu-mir-183, mmu-mir-194-1, mmu-mir-200b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-183, hsa-mir-181a-1, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-140, hsa-mir-194-1, 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-15a, mmu-mir-21a, mmu-mir-29a, mmu-mir-96, mmu-mir-34a, mmu-mir-135b, hsa-mir-200c, hsa-mir-181b-2, mmu-mir-17, mmu-mir-200c, mmu-mir-181a-1, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-181b-1, mmu-mir-181c, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-376c, hsa-mir-376a-1, mmu-mir-376a, hsa-mir-135b, mmu-mir-181b-2, mmu-mir-376b, dre-mir-34a, dre-mir-181b-1, dre-mir-181b-2, dre-mir-182, dre-mir-183, dre-mir-181a-1, 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-15a-1, dre-mir-15a-2, dre-mir-17a-1, dre-mir-17a-2, dre-mir-21-1, dre-mir-21-2, dre-mir-29a, 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-140, dre-mir-181c, dre-mir-194a, dre-mir-194b, dre-mir-200b, dre-mir-200c, hsa-mir-376b, hsa-mir-181d, hsa-mir-507, dre-let-7j, dre-mir-135b, dre-mir-181a-2, hsa-mir-376a-2, mmu-mir-376c, dre-mir-34b, dre-mir-34c, mmu-mir-181d, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-let-7k, dre-mir-181a-4, dre-mir-181a-3, dre-mir-181a-5, dre-mir-181b-3, dre-mir-181d, mmu-mir-124b
The data verified that two miRNAs, miR-29a and -34a, which have been implicated in apoptotic pathways, are up-regulated and the two miRNAs, miR-181 and -183, which have been shown to have roles in proliferation and differentiation, are down-regulated While it is believed that a major cause of ARHL is the death of hair cells, other age-related changes in the central auditory pathways cannot be ruled out. [score:7]
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