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214 publications mentioning hsa-mir-192 (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-192. 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: 385
Indeed, renal cancers were found to have a large dynamic range of miR-192 expression (Supplementary Fig. 6a), and patients with tumours expressing low levels of miR-192 had significantly worse OS (median OS of 69 versus 147 months for tumours with low versus high miR-192 expression, respectively, P<0.005; percentile cutoff=0.29; Fig. 5a). [score:7]
A total of 158 transcription factors were predicted to regulate more than five angiogenic factors with 13 of them predicted to be direct targets of miR-192 by at least four miRNA target prediction algorithms (Supplementary Table 4 and Fig. 2c). [score:7]
Consistent with these findings, miR-192 transfection in S KOV3ip1 and HeyA8 cells resulted in a significant downregulation of several important angiogenic factors including IL6, IL8 and FGF2 levels (75, 80 and 50% decrease, respectively; Supplementary Fig. 1e), while only a minimal downregulation of these factors was observed following miR-194 treatment (Supplementary Fig. 1f). [score:7]
However, we observed strong negative correlations between methylation levels of four probes, which target miR-192 directly and overall miR-192 expression levels in multiple cancer types (Supplementary Table 5). [score:6]
The identification of miR-192 as a common upstream regulator of these two key transcription factors is thus of high importance given that to date, mechanisms of EGR1 and HOXB9 regulation are still largely unknown and no effective therapeutic means has been developed to regulate their expression. [score:6]
For both genes, mutation of the predicted binding site (Supplementary Fig. 2h) abrogated knockdown, indicating that EGR1 and HOXB9 are both direct miR-192 targets. [score:6]
As an alternative, to assess whether miR-192 expression is indeed regulated by methylation in ovarian cancer, we treated the S KOV3ip1 cells with azacitidine, a methylation inhibitor. [score:6]
In contrast to empty lentiviral vector (EV)-transduced S KOV3ip1 cells where miR-192 treatment resulted in a 60% reduction in tube formation potential, only 30 and 20% downregulation in tube formation potential was achieved using conditioned media collected from EGR1- and HOXB9 -expressing S KOV3ip1 cells following miR-192 treatment, respectively (Fig. 3b). [score:6]
As upregulation of the compensatory pro-angiogenic signalling cascades has been shown to play a crucial role in resistance to anti-angiogenic therapy, our finding of the global anti-angiogenic effect of miR-192 represents a promising new approach for targeting tumour angiogenesis. [score:6]
Further examination of all pro-angiogenic factors that have log [2] expression levels above 8 (control miRNA -treated cells) in the microarray data set revealed the ability of miR-192 to globally downregulate angiogenic pathways (Fig. 2b). [score:6]
This rescue of pro-angiogenic factor expression in EGR1 and/or HOXB9 expressing cells resulted in significant abrogation of the anti-angiogenic effects of miR-192. [score:5]
Tumoral miR-192 expression levels showed significant inverse correlations with EGR1 (P<0.001) and HOXB9 (P<0.05) protein expression (n=98, Supplementary Fig. 2f). [score:5]
Upon examining expression levels of these genes and miR-192 in the NCI-60 cell line database 13, we found TWIST1 to have the most significant negative correlation with miR-192 expression (Supplementary Fig. 4c). [score:5]
In contrast, miR-192 was expressed at a significantly lower level in the mesenchymal group (P=0.02), but the difference in expression between the epithelial and mesenchymal groups was marginal. [score:5]
We demonstrated that the potent anti-angiogenic effect of miR-192 stems from its ability to globally downregulate angiogenic pathways in cancer cells through regulating two key transcription factors, EGR1 and HOXB9 (Fig. 6). [score:5]
At 48 h following miR-192 transfection, EGR1 and HOXB9 mRNA levels were the most downregulated by approximately 75% (Fig. 2d). [score:4]
On the basis of findings described in the manuscript, TWIST1 downregulates miR-192 levels in cancer cells, leading to increased HOXB9 and EGR1 levels. [score:4]
Given the ability of miR-192 to globally downregulate the angiogenic pathways, it provides a central node to potently block tumour angiogenesis. [score:4]
This effect was not fully rescued by replacing IL6 and IL8, two cytokines that are most downregulated by miR-192 treatment, in the conditioned media (Supplementary Fig. 2j). [score:4]
We subsequently hypothesized that miR-192 mediates its global anti-angiogenic effect by targeting transcription factors that regulate multiple angiogenic molecules. [score:4]
The downregulation of EGR1 and HOXB9 by miR-192 was further confirmed in another ovarian cancer cell line, HeyA8 (Supplementary Fig. 2d). [score:4]
Incubation of the RF24 cells with conditioned media collected from the S KOV3ip1 cells treated with miR-215, a miRNA closely associated with miR-192, did not significantly inhibit tube formation, demonstrating the unique ability of miR-192 to regulate tumour angiogenesis (Supplementary Fig. 1g). [score:4]
Similar to ovarian cancer, miR-192 treatment mediated a robust downregulation of EGR1 and HOXB9 levels (Fig. 5b) and significant decreases in several angiogenic factors including IL6, IL8 and EFNA1 (Fig. 5c); consistent with the pattern observed after si EGR1/si HOXB9 treatment (Supplementary Fig. 6b,c). [score:4]
Of note, direct expression of miR-192 in RF-24 cells resulted in modest reduction in their tube formation potential (Supplementary Fig. 1h). [score:4]
We, thus, hypothesized that TWIST1, a transcription factor commonly upregulated in hypoxia, can act as a transcriptional repressor for miR-192. [score:4]
The EGR1 and HOXB9 protein levels were also both significantly downregulated following miR-192 transfection in both the cell lines examined (Supplementary Fig. 2e). [score:4]
Notably, EGR1 and HOXB9 were both regulated by miR-192 but had different downstream targets. [score:4]
Pathway enrichment analysis using Netwalker 12 showed that miR-192 significantly alters the angiogenesis pathway (P=7.8 × 10 [−6], ) and 6 out of the 15 most significantly downregulated genes are pro-angiogenic (Fig. 2a). [score:4]
To date, the biological function of miR-192 has been reported predominantly in the areas of cell survival 26 and metastasis through direct targeting of MDM2, TYMS, SIP1 or ZEB2 (refs 21, 24, 27, 28, 29). [score:4]
Ingenuity IPA software was used to identify the genes that are most significantly downregulated following the miR-192 treatment. [score:4]
MiRwalk database 57 was subsequently used to identify transcription factors that can be directly targeted by miR-192. [score:4]
PTGIS and IL6 were among the top molecules identified to have the strongest negative correlation with tumoral miR-192 expression (levels increased by 84%, P=2.32 × 10 [−8] and 43%, P=0.018 in tumours with low miR-192 compared with the ones with high miR-192, respectively; miR-192 percentile cutoff of 0.26 was used for defining high versus low expression). [score:4]
Importantly, restoring EGR1 abrogated the miR-192 induced downregulation of EFNA1 and CXCL1. [score:4]
IL6, IL8 and EFNA1 are among the angiogenic factors that are most significantly downregulated by miR-192 in A498 cells. [score:4]
We next assessed the ability of miR-192 to target these transcription factors in S KOV3ip1 cells. [score:3]
Stable lentiviral miRNA vectors were purchased from Thermo Scientific (HMR5887 for non -targeting control and V1SMHS_000952 for miR-192). [score:3]
As miR-192 expression has been previously reported to be associated with VEGF levels 19, we assessed both miR-192 and miR-194 levels in tumours treated with B20. [score:3]
Of these genes, ZEB1, ETV1 and TWIST1 were found to have significant correlations with miR-192 expression in TCGA ovarian database (n=559, P<0.0001). [score:3]
The cells were incubated with conditioned media collected from stable S KOV3ip1 control miRNA or miR-192 expressing cells or from ovarian or renal cancer cells treated control miRNA, miR-192, miR-194 or miR-215 mimics. [score:3]
We first introduced lentiviral vectors expressing control miRNA (S KOV3ip1-NC) or miR-192 (S KOV3ip1-miR-192) into S KOV3ip1 cells. [score:3]
We examined miR-192 expression in mesenchymal versus epithelial subtypes of ovarian tumours using TCGA ovarian data set 14. [score:3]
In this patient cohort, low tumoral miR-192 expression was also found to be significantly associated with worse OS (3.86 versus 6.85 years, log-rank P=0.001, Supplementary Table 2), consistent with the results from TCGA ovarian data set. [score:3]
Only minimal decreases in MVD and increases in the extent of pericyte coverage of residual blood vessels were observed in tumours expressing both EGR1 and HOXB9 after the miR-192 treatments (Fig. 4h), emphasizing the key roles EGR1 and HOXB9 play in mediating the anti-angiogenic effects of miR-192. [score:3]
Generation of miR-192/EGR1/HOXB9 expressing cell lines. [score:3]
Zinc Finger E-Box Binding Homeobox 2 (ZEB2), a known miR-192 target 11, was used as a positive control for this experiment (Supplementary Fig. 2c). [score:3]
However, a luciferase assay using the entire 3′-untranslated region (3′-UTR) of IL6 revealed the lack of direct binding of miR-192 to IL6 (Supplementary Fig. 2b). [score:3]
In contrast, expression of both EGR1 and HOXB9 was necessary to completely abrogate the effects of miR-192 on IL6, IL8, and IL1β levels, with a rebound effect observed with IL1β (Fig. 3a). [score:3]
Since clear-cell renal carcinomas are highly angiogenic 20, and anti-angiogenic agents are the mainstay of treatment for kidney cancer, we hypothesized that miR-192 treatment may show therapeutic benefit in renal cancer patients with low endogenous tumoral miR-192 expression. [score:3]
No statistically significant differences in miR-192 or miR-194 expression were observed between normal versus tumoral endothelial cells (Supplementary Fig. 1a). [score:3]
Effect of miR-192 expression on mesenchymal phenotype. [score:3]
The number of tumour nodules was also decreased in mice bearing miR-192 -expressing tumours (Supplementary Fig. 5c). [score:3]
This further corroborates the paracrine effect of tumoral miR-192 expression on blood vessel maturation. [score:3]
The Spearman test was used to assess the correlation between miR-192 and gene expression or angiogenic scores. [score:3]
Indeed, pathway analysis of genes that are negatively associated with miR-192 expression in TCGA ovarian data set also revealed angiogenesis as one of the major pathways affected by this miRNA (Supplementary Table 3). [score:3]
After eliminating the data from replicate samples, we plotted miR-192 expression against the beta value for each of the associated methylation probes (cg02258444-11-64658622, cg09349409-11-64658765, cg18262830-11-64658819 and cg27083891-11-64658726). [score:3]
Using the data set described in Supplementary Table 2, we further assessed the correlation between miR-192 and EGR1 or HOXB9 protein expression levels in human ovarian epithelial tumours. [score:3]
Dual EGR1 and HOXB9 expression resulted in complete rescue of the anti-angiogenic effect of miR-192. [score:3]
As such, it is anticipated that patients whose tumours have low miR-192 expression would greatly benefit from miR-192 therapy. [score:3]
To assess the therapeutic effect of miR-192 in renal cancer, we injected A498 renal cancer cells expressing an EV or both EGR1 and HOXB9 (A498-EV and A498- EGR1+ HOXB9, respectively) into the subcapsular space in the kidneys of mice. [score:3]
To study the roles of miR-192 and miR-194 in tumour angiogenesis, we first examined the expression levels of these miRNAs in endothelial cells isolated from human normal ovaries or HGSCs. [score:3]
We subsequently performed Spearman correlation analyses between miR-192 expression and the beta values for each probe. [score:3]
We, thus, reasoned that while TWIST1 and miR-192 are closely linked with each other, the survival benefit that we observed with miR-192 is not purely a reflection of the difference in TWIST1 expression. [score:3]
Statistical analysis for tumoral miR-192, EGR1 and HOXB9 expression in patients was performed as previously described 55 56. [score:3]
In contrast, the tumours expressing EGR1 and HOXB9 proteins failed to respond to miR-192 therapy, again demonstrating the central role of these two proteins in miR-192 -mediated anti-tumour effect. [score:3]
We first correlated miR-192 expression with copy number alteration and promoter methylation in each of the TCGA data sets (21 cancer types). [score:3]
for tumoral miR-192, EGR1 and HOXB9 expression in patients was performed as previously described 55 56. [score:3]
We next assessed whether the anti-angiogenic effect of miR-192 can be abrogated by EGR1 and/or HOXB9 expression in S KOV3ip1 tumours. [score:3]
The expression levels of miR-192 were determined using CellProfiler 2.0 software to establish the staining intensity threshold levels and to quantify the number of positively stained cancer cells per HPF (× 200 magnification) 16. [score:3]
Collectively, these results indicate that significant therapeutic benefit can be derived from miR-192 -mediated inhibition of multiple pro-angiogenic pathways simultaneously. [score:3]
The expression of both EGR1 and HOXB9 in tumours completely abrogated the anti-tumour effect of miR-192. [score:3]
In contrast to the S KOV3ip1-EV tumours where miR-192 treatment resulted in a 90% reduction in tumour burden, only 65 and 30% reduction in tumour burden was observed for tumours expressing EGR1 and HOXB9, respectively (Fig. 4g). [score:3]
To assess whether EGR1 and HOXB9 are direct targets of miR-192, luciferase assays using the entire 3′-UTR were performed. [score:3]
Importantly, tumoral miR-192 expression remained an independent predictor of survival following the multivariate analysis accounting for age, stage, grade and extent of cytoreduction (P<0.001, Cox proportional-hazards mo del). [score:3]
MiR-192 mediates global downregulation of angiogenic factors. [score:3]
There were two treatment groups: (1) non -targeting control (NC) miRNA-DOPC or (2) miR-192-DOPC. [score:3]
A matrix similarity score cutoff of 0.9 or 0.95 were used for identifying transcription factors that can bind directly to the promoter regions of the pro-angiogenic genes or miR-192, respectively. [score:2]
The expression of miR-192 and TWIST1 were compared between the mesenchymal and epithelial groups using the Wilcoxon rank-sum test. [score:2]
Next, we investigated the potential mechanism by which miR-192 is downregulated in tumours. [score:2]
Given the role of TWIST1 in regulating epithelial–mesenchymal transition, we further assessed whether there is a relationship between miR-192 level and epithelial morphology of ovarian tumours. [score:2]
To examine other potential regulators of miR-192, we used Genomatix software to predict potential transcription factors that can bind to the miR-192 promoter region. [score:2]
Using an integration of systems -based bioinformatics coupled with experimental mo dels, we rigorously document here the central role of miR-192 in regulating tumour angiogenesis. [score:2]
How to cite this article: Wu, S. Y. et al. A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer. [score:2]
To identify the dominant angiogenic factors regulated by miR-192, we first examined the correlation between miR-192 and mRNA level of 65 angiogenic factors in TCGA ovarian cancer data set (). [score:2]
These results indicate the potential role of TWIST1 in regulating miR-192 in ovarian tumours. [score:2]
Collectively, our data provide an important advance in understanding the importance and mechanism of miR-192 in regulating tumour angiogenesis. [score:2]
Upstream regulation of miR-192. [score:2]
Previous reports have documented the ability of miR-192 to negatively regulate factors such as VEGFA 34 or ICAM1 (ref. [score:2]
Tumoral miR-192 expression levels showed significant inverse correlation with blood vessel density, with a 68% reduction in MVD in tumours with high levels of miR-192 compared with those with low tumoral levels of miR-192 (percentile cutoff=0.33, P<0.0001, Fig. 1e). [score:2]
Kaplan–Meier survival curves were generated and compared with the use of a log-rank statistic to assess the effect of tumoral miR-192, EGR1 or HOXB9 expression on overall survival. [score:2]
The anti-angiogenic and anti-tumour effects of miR-192 were found to be much more robust than that achieved with anti-VEGF antibody. [score:1]
Supplementary Data 1. Supplementary Data 2. Supplementary Data 3. Supplementary Data 4. Integrative analyses identified miR-192 as a key player in tumour angiogenesis. [score:1]
Matrigel was mixed with VEGF alone (positive control) or conditioned media collected from S KOV3ip1 cells treated with control miRNA or miR-192. [score:1]
We showed that the ability of miR-192 to reduce blood vessel density was more profound than that observed with the B20 treatment. [score:1]
Given the anti-angiogenic property of miR-192, we next examined the effect of miR-192 on tumour progression in orthotopic mouse mo dels of ovarian cancer. [score:1]
The putative miR-192 binding sites for a panel of transcription factors, including EGR1 and HOXB9, were assessed bioinformatically using several algorithms 16. [score:1]
There were four treatment groups: (1) Phosphate-buffered saline (PBS), (2) B20-4.1.1, (3) NC miRNA-DOPC and (4) miR-192-DOPC. [score:1]
The stained slides were scored by two investigators blinded to patient survival information or miR-192 expression levels. [score:1]
To assess whether miR-192 can also affect tumour angiogenesis in other cancer types, we examined the level of miR-192 in tumours across 19 cancer types using TCGA data sets (Supplementary Fig. 6a). [score:1]
Schematic representation of mechanisms by which miR-192 mediates its anti-angiogenic function. [score:1]
This miR-192 -mediated anti-angiogenic effect was significantly reduced following the rescue of EGR1 and/or HOXB9 levels by lentiviral transduction in these renal cancer cells (Fig. 5c,d, Supplementary Fig. 6d). [score:1]
This indicates that miR-192 mediates its anti-angiogenic effect mainly from its effect on cancer cells. [score:1]
We further presented several lines of pre-clinical evidence demonstrating the marked therapeutic potential of miR-192 in ovarian and renal cancer mo dels without causing toxicity in normal organs. [score:1]
Next, EGR1 and HOXB9 constructs which lack the 3′-UTR component were used to generate cells that are insensitive to miR-192 treatment. [score:1]
MiRNA in situ hybridizationTisue microarray samples for ovarian tumours were used for miR-192 quantification. [score:1]
We next sought to compare the anti-angiogenic and anti-tumour effect between miR-192 and murine anti-VEGF antibody, B20-4.1.1 (equivalent to bevacizumab, a clinically used anti-VEGF agent for the treatment of multiple cancer types). [score:1]
Importantly, in S KOV3ip1-EV tumours, tumour vasculature following the miR-192 treatment was significantly less permeable than the control miRNA group (Supplementary Fig. 5n). [score:1]
Collectively, both the in vitro and in vivo results shown here were consistent with those observed in ovarian cancer mo dels, indicating the broad implications of modulating miR-192 in different cancer types. [score:1]
The mice were then treated with control miRNA-DOPC or miR-192-DOPC twice weekly for 4 weeks. [score:1]
We report here that EGR1 and HOXB9 transcription factors are responsible for mediating the broad anti-angiogenic function of miR-192, since restoration of EGR1 and HOXB9 completely rescued this effect. [score:1]
We subsequently injected S KOV3ip1-NC or S KOV3ip1-miR-192 cells into the peritoneal cavity of athymic nude mice (n=10 per group). [score:1]
In vivo effects of miR-192 on ovarian cancer progressionGiven the anti-angiogenic property of miR-192, we next examined the effect of miR-192 on tumour progression in orthotopic mouse mo dels of ovarian cancer. [score:1]
Mice bearing S KOV3ip1 tumours were treated with control miR or miR-192 containing DOPC nanoliposomes. [score:1]
Mutated constructs have predicted miR-192 binding site deleted. [score:1]
For EGR1 and HOXB9, mutated constructs were also synthesized with the predicted miR-192 binding sites deleted (Supplementary Fig. 2h). [score:1]
For the miRNA-Seq data sets, the following MIMAT numbers were analysed: MIMAT0000259 (hsa-miR-182-5p), MIMAT0000222 (hsa-miR-192-5p), MIMAT0002868 (hsa-miR-522-3p), MIMAT0018937 (hsa-miR-378g), MIMAT0003326 (hsa-miR-663a), MIMAT0000258 (hsa-miR-181c-5p), MIMAT0000318 (hsa-miR-200b-3p), MIMAT0000095 (hsa-miR-96-5p), MIMAT0014999 (hsa-miR-378b), MIMAT0005870 (hsa-miR-1206), MIMAT0000266 (hsa-miR-205-5p), MIMAT0000460 (hsa-miR-194-5p) and MIMAT0000440 (hsa-miR-191-5p). [score:1]
Anti-angiogenic and therapeutic effects of miR-192 in orthotopic mouse mo dels of ovarian cancer. [score:1]
We showed that miR-192 significantly enhanced survival (P=0.009, Supplementary Fig. 5g). [score:1]
High tumoral miR-192 and miR-194 correlated with prolonged overall survival (OS; both P<0.05). [score:1]
The anti-angiogenic effect of miR-192. [score:1]
After transfecting the S KOV3ip1 cells with either control miRNA or miR-192 (40 nM), cells were exposed to serum-free media for 48 h. We then collected the supernatants and centrifuged them to remove cells. [score:1]
The anti-angiogenic and antitumour effects of miR-192 in renal tumours. [score:1]
Importantly, miR-192-DOPC treatment resulted in significant reduction in blood vessel density as well as increased pericyte coverage of residual blood vessels (Supplementary Fig. 5k). [score:1]
Similar to the results obtained previously, miR-192-DOPC treatment reduced the tumour burden by approximately 85% (S KOV3ip1 mo del, Supplementary Fig. 5h). [score:1]
To systematically examine the molecular mechanisms by which miR-192 mediates its anti-angiogenic effect, a microarray was performed following miR-192 transfection in the S KOV3ip1 cells (). [score:1]
MiR-192 mediates its anti-angiogenic effects through regulating EGR1 and HOXB9. [score:1]
The ovarian and renal cancers are both highly angiogenic cancer types, with high miR-192 levels correlating with significantly improved patient survival. [score:1]
Systemic delivery of miR-192 using DOPC nanoliposomes represents a potent means of blocking tumour angiogenesis and reducing tumour growth. [score:1]
EGR1 and HOXB9 constructs that lack the 3′-UTR component were used to generate cells that are insensitive to miR-192 treatment. [score:1]
Given the ability of miR-192 to modulate tumour angiogenesis, we next assessed the feasibility of treating ovarian tumours with combined therapy of miR-192 and topotecan, a chemotherapeutic agent with anti-angiogenic activity 18. [score:1]
The tissue slides were incubated with double-DIG -labelled mercury LNA miR-192 probe (Exiqon) for 2 h at 52 °C. [score:1]
Functional pathways altered by miR-192. [score:1]
We introduced miR-192 mimics into two renal cancer cell lines, RCC4 and A498. [score:1]
The S KOV3ip1 cells were treated with control miRNA or miR-192 (40 nM) using RNAiMAX transfection reagent. [score:1]
Starting 7 days following the cell implantation, the mice were treated with DOPC nanoliposome- delivered control miRNA or miR-192 twice a week. [score:1]
This degree of increase in miR-192 level was significantly lower than that observed from miR-192-DOPC treatment (Supplementary Fig. 5j). [score:1]
Minimal rescue of miR-192 levels was observed following the azacitidine treatment in HeyA8 cells (Supplementary Fig. 4a,b). [score:1]
In contrast, minimal difference in vessel permeability was observed between S KOV3ip1- EGR1+ HOXB9 tumours treated with control miRNA and miR-192. [score:1]
Importantly, we showed that miR-192 is able to mediate profound anti-angiogenic and anti-tumour effects in vivo, independent of its impact on cancer cell growth. [score:1]
For the survival experiment, mice bearing S KOV3ip1 tumours were treated with control miRNA-DOPC or miR-192-DOPC twice a week starting at 1 week following the tumour cell injection. [score:1]
Here, using large-scale patient data sets, we demonstrated that decreased tumoral miR-192 levels are associated with increased angiogenesis and poor overall survival in patients with high-grade serous ovarian or renal clear cell carcinomas. [score:1]
These findings further point to the role of tumour microenvironment in mediating the anti-tumour effects of miR-192. [score:1]
Using the DOPC nanoliposomal platform, which is currently being tested in clinical trials, we showed that miR-192 can mediate potent anti-angiogenic and anti-tumour effects in multiple orthotopic mouse mo dels of ovarian and renal cancer. [score:1]
We further showed that miR-192-DOPC treatment resulted in a significant increase in the number of apoptotic cells in tumours (P<0.001, Supplementary Fig. 5l). [score:1]
In vivo effects of miR-192 on ovarian cancer progression. [score:1]
Effect of miR-192 on angiogenesis. [score:1]
The ability of TWIST1 to bind to the promoter region of miR-192 was further assessed using a with an anti-TWIST1 antibody. [score:1]
The S KOV3ip1 cells were transfected with FuGENE HD reagent in a 96-well plate with control miRNA or miR-192 (40 nM) along with the 3′-UTR reporter constructs, and Cypridina TK control construct (pTK-Cluc) as per the manufacturer's protocol 50. [score:1]
Effects of miR-192 on angiogenesis in renal cancer. [score:1]
Unexpectedly, no rescue of miR-192 level was observed following the azacitidine treatment in the S KOV3ip1 cells (Supplementary Fig. 4a), despite successful demethylation of the miR-192 promoter region (Supplementary Fig. 4b). [score:1]
Next, a survival experiment was carried out to assess the impact of miR-192 on survival in mice (n=7). [score:1]
Having established the anti-tumour effect of miR-192 in vivo, we next tested the feasibility of using miR-192 therapeutically to treat ovarian cancer. [score:1]
Tisue microarray samples for ovarian tumours were used for miR-192 quantification. [score:1]
Moreover, histopathological examination of major organs following 4 weeks of miR-192-DOPC therapy revealed no abnormalities (Fig. 4d). [score:1]
PCR -based quantification of fold enrichment in TWIST1, EGR1 or HOXB9 binding to miR-192, IL6, EFNA1, IL1β or ITGA6 promoter regions was subsequently performed. [score:1]
Genomic analyses of S KOV3ip1 cells treated with control miRNA and miR-192. [score:1]
Our systematic analyses thus identified miR-192 as a key player in tumour angiogenesis (Fig. 1f). [score:1]
Indeed, when we introduced TWIST1 into both S KOV3ip1 and HeyA8 cells, miR-192 levels were significantly decreased (Supplementary Fig. 4d). [score:1]
RF-24, human endothelial cells, were then exposed to conditioned media obtained from control miRNA, miR-192 or miR-194 -treated S KOV3ip1 cells (48 h post transfection). [score:1]
To further demonstrate the impact of miR-192 on angiogenesis in clinical samples, an independent set of patient tumours (n=128) were used to assess the correlation between miR-192 and tumour MVD. [score:1]
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[+] score: 323
Consistent with the expression pattern in TCGA, miR-192 expression was also downregulated, whereas SLC39A6 expression was upregulated in the HCC samples (Figure 6A). [score:13]
miR-192 inhibitor transfection into MHCC-97L cells upregulated SNAIL expression and downregulated E-cadherin expression (right). [score:13]
The restoration of SLC39A6 expression in cells stably expressing miR-192 blocked the miR-192 -induced suppression of migration and invasion (Figure 4C, Supplementary Figure 3E) and knockdown of SLC39A6 abolished migration and invasion elevation in miR-192 inhibited cells (Figure 4C), indicating that SLC39A6 mediated the suppressive effects of miR-192 on HCC migration and invasion. [score:12]
miR-192 expression negatively correlated with SLC39A6 expression (Figure 6B), which suggested that upregulation of SLC39A6 might be due to downregulation of miR-192 in HCC. [score:11]
Moreover, SLC39A6 expression was inversely associated with miR-192 expression in two independent HCC samples, which suggested that SLC39A6 upregulation in HCC might be caused by miR-192 downregulation. [score:11]
Furthermore, re -expression of SLC39A6 in cells stably expressing miR-192 reversed SNAIL and E-cadherin expression levels alteration induced by miR-192 and knockdown of SLC39A6 after miR-192 inhibitor transfection also abrogated protein change of SNAIL and E-cadherin (Figure 5C). [score:10]
miR-192 was previously reported to inhibit the liver metastasis of colon cancer through targeting Bcl-2, Zeb-2, and VEGFA [31], to suppress tumor progression in renal cell carcinoma [32], to inhibit cell proliferation and induce apoptosis in lung cancer [33], and to be a biomarker of distant metastasis in gastric cancer [34]. [score:9]
Taken together, miR-192 expression decreased stepwise in HCC cells with gradually increasing metastatic potential and was downregulated in HCC samples, indicating that miR-192 might act as a metastasis suppressor in HCC. [score:8]
We also found that miR-192 decreased SNAIL expression by downregulating SLC39A6 expression in HCC cells. [score:8]
Remarkably, SNAIL expression decreased and E-cadherin expression increased following SLC39A6 downregulation in miR-192 mimic -transfected cells (Figure 5B). [score:8]
miR-192 inhibited HCC cell migration and invasion by downregulating SLC39A6 expression and inactivating the SLC39A6/SNAIL signaling pathway. [score:8]
Figure 3(A) Intersection of TargetScan predicted miR-192 targets and upregulated genes in TCGA dataset. [score:8]
Correlation analysis between SLC39A6, IGDCC4, SRGAP3 and miR-192 in TCGA dataset revealed that SLC39A6 expression negatively correlated with miR-192 expression, while IGDCC4 and SRGAP3 expression did not (Figure 3C, Supplementary Figure 3A). [score:7]
To explore the molecular mechanisms by which miR-192 inhibited HCC cell metastasis, we predicted 160 potential targets of miR-192 in TargetScan (http://www. [score:7]
The expression of E-cadherin, a downstream effector of SNAIL [37], was upregulated by miR-192. [score:6]
We further identified miR-192 as a metastasis suppressor of HCC and SLC39A6, which is an oncogene involved in different types of cancer [17– 22], as a direct and functional target for miR-192 in HCC. [score:6]
In this study, we found that miR-192 expression decreased stepwise in cell lines with gradually increasing metastatic potential and was downregulated in HCC tissues of 101 independent pairs of HCC patients and TCGA dataset. [score:6]
These results suggested that miR-192 might regulate SNAIL and E-cadherin expression by targeting SLC39A6. [score:6]
Moreover, the SLC39A6 protein level was downregulated in miR-192 -overexpressing cells (Figure 3E). [score:6]
Among these differentially expressed miRNAs, miR-192 was often downregulated in HCC. [score:6]
Moreover, restoration of SNAIL expression reversed the miR-192 -induced suppression of HCC cell migration and invasion (Figure 5D). [score:5]
Consistent with these results, miR-192 inhibitor transfection increased SLC39A6 protein levels and altered SNAIL and E-cadherin expression levels (Figure 5B). [score:5]
These data suggested that miR-192 targeted the SLC39A6/SNAIL pathway to suppress HCC cell migration and invasion. [score:5]
Importantly, HCC patients with higher miR-192 expression levels had better overall survival than the group with lower miR-192 expression levels (Figure 6C). [score:5]
miR-192 decreased SNAIL expression by targeting SLC39A6 in HCC cells. [score:5]
Restoration of SNAIL expression could antagonize the inhibition of miR-192. [score:5]
miR-192 mimic transfection significantly inhibited HCC cell migration and invasion in vitro (Figure 2A and 2B, Supplementary Figure 2B), whereas miR-192 inhibitor transfection promoted HCC cell migration and invasion (Figure 2C). [score:5]
Moreover, stably overexpressed miR-192 (Supplementary Figure 2C) resulted in the suppression of migration and invasion in HCC-LM3 and Huh-7 cells (Figure 2A and 2B). [score:5]
Most importantly, patients with higher miR-192 expression levels had better overall survival rates than did patients with lower miR-192 expression levels (Figure 1E). [score:5]
Figure 2miR-192 suppressed HCC cell metastasis in vitro and in vivo(A) Representative results of the Transwell migration assays showing the effect of miR-192 expression on the migratory abilities of HCC-LM3 and Huh-7 cells (unpaired Student's t-test, mean ± SEM; * P < 0.05; ** P < 0.01; *** P < 0.001). [score:4]
In addition, SLC39A6 was identified as a direct downstream target of miR-192 in HCC cells. [score:4]
The luciferase activity of the wild type 3′ UTR of SLC39A6 was downregulated in the presence of miR-192, while the luciferase activity of the mutant 3′ UTR of SLC39A6 remained unchanged (Figure 3D). [score:4]
miR-192 was downregulated in metastatic HCC cell lines and. [score:4]
Only three genes, SLC39A6, IGDCC4 and SRGAP3, were downregulated after miR-192 transfection in two cell lines (Figure 3B). [score:4]
miR-192 was downregulated in metastatic HCC cell lines and HCC tissues. [score:4]
SLC39A6 was a direct downstream target of miR-192 in HCC cells. [score:4]
miR-192 suppressed HCC cell metastasis in vitro and in vivoTo investigate the function of miR-192 in HCC, we first determined the intrinsic expression levels of miR-192 in seven HCC cell lines (Supplementary Figure 2A). [score:3]
Then, we determined the expression of 10 candidates by q-PCR after miR-192 mimic transfection. [score:3]
Importantly, better overall survival rates of HCC patients correlated with higher miR-192 expression levels. [score:3]
Altogether, miR-192 inhibited the invasion and metastasis of HCC cells in vitro and in vivo. [score:3]
These findings confirmed that miR-192 was an essential suppressor of metastasis in HCC. [score:3]
miR-192 suppressed HCC cell metastasis in vitro and in vivo. [score:3]
Elevated miR-192 expression did not affect HCC cell growth (Supplementary Figure 2D). [score:3]
Multivariate analysis indicated that low miR-192 expression was a distinguishing and independent risk factor of HCC patients, with a higher hazard ratio than any other variables. [score:3]
Univariate analyses using the Cox hazard regression mo del identified low miR-192 expression, tumor size, differentiation and metastasis as prognostic indicators of overall survival for HCC patients (Figure 6D, Table 1). [score:3]
miR-192 inhibited SLC39A6/SNAIL/E-cadherin pathways in HCC cells. [score:3]
Figure 6(A) Left, determination of miR-192 expression levels by q-PCR in an independent cohort of 101 paired HCCs and adjacent non-tumor tissues (paired Student's t-test). [score:3]
miR-192 and SLC39A6 might be useful indicators for HCC patient outcomes, and the miR-192/SLC39A6/SNAIL pathway might be a promising therapeutic target for HCC treatment. [score:3]
< = 20) 1.892 0.980–3.655 0.058 miR-192 expression (low vs. [score:3]
These results revealed a significant contribution of higher miR-192 expression to better HCC patient outcomes and indicated that miR-192 was an independent and significant prognostic factor for HCC patients. [score:3]
The miR-192 mimic and inhibitor were synthesized by RiboBio (Guangzhou, China). [score:3]
This unbiased interrogation of this cell mo del identified miR-192 as a potential metastasis suppressor in HCC. [score:3]
Multivariate analysis further demonstrated that low miR-192 expression was an independent and significant risk factor of overall survival for HCC patients (hazard ratio, 3.739; 95% CI, 1.127–12.407; P = 0.031; Table 2). [score:3]
HCC-LM3, Huh-7 and SK-Hep-1 cell lines were used to analyze the effects of miR-192 overexpression. [score:3]
Moreover, miR-192 significantly suppressed HCC cell invasion and metastasis in vitro and in vivo. [score:3]
< = 5cm) 1.651 0.810–3.366 0.167 miR-192 expression (low vs. [score:3]
Moreover, clinical significance analysis of TCGA data showed that miR-192 expression levels were lower in HCC patients with vascular cell invasion compared with HCC patients without vascular cell invasion (Figure 1D). [score:2]
The mutant miR-192 binding sequence was generated in the seed region. [score:1]
To further determine the effect of miR-192 on metastasis in vivo, Huh-7-miR-192 and Huh-7-vector stable cell lines were transplanted into the livers of nude mice. [score:1]
Thus, miR-192 could act as a useful indicator for HCC outcomes. [score:1]
To further evaluate the clinical significance of the miR-192/SLC39A6 axis in HCC, we determined miR-192 and SLC39A6 expression levels in another independent cohort of tumors and adjacent non-tumor tissues from 101 HCC patients. [score:1]
The entire coding sequence of SLC39A6 and pre-miR-192 were amplified and cloned into the pWPXL vector, which was obtained from Addgene (http://www. [score:1]
To investigate the function of miR-192 in HCC, we first determined the intrinsic expression levels of miR-192 in seven HCC cell lines (Supplementary Figure 2A). [score:1]
Taken together, these results indicated that, was negatively correlated with overall survival of HCC patients and functioned as a downstream mediator of miR-192. [score:1]
Prognostic significance of miR-192 in HCC patients. [score:1]
miR-192 was an independent predictor for HCC patient outcomes. [score:1]
The numbers of intrahepatic metastatic nodules and the incidence of intrahepatic metastasis were significantly lower in the miR-192 group than were those in the vector group (Figure 2D and 2E). [score:1]
However, the function of miR-192 in HCC has remained unexplored. [score:1]
HEK-293T cells cultured in a 96-well plate were co -transfected with 10 nM NC or miR-192 mimic, 2 ng pRL-TK (Promega, Madison, WI, USA) and 10 ng firefly luciferase reporter containing the wildtype or mutant 3′UTR of SLC39A6. [score:1]
Notably, six miRNAs (miR-489, miR-194–3p, miR-200a-3p, miR-30e-3p, miR-192, and miR-574–3p) were identically decreased in both our microarrays and The Cancer Genome Atlas (TCGA) dataset (Supplementary Table 1, Figure 1B). [score:1]
Importantly, miR-192 was negatively associated with metastasis and poor prognosis and could be an independent indicator for HCC patient outcome. [score:1]
In conclusion, we newly identified miR-192/SLC39A6/SNAIL as an important signaling pathway that governed HCC metastasis. [score:1]
The chi-square (χ [2]) test was used to evaluate the correlation between metastasis incidence and miR-192 expression in animal mo del. [score:1]
Representative images of the histological examination of mouse livers for primary tumors and metastatic nodules from Huh-7-vector and Huh-7-miR-192 cells (D), and the incidence of intrahepatic metastasis in the two groups of this mouse mo del (E). [score:1]
Huh-7-miR-192 and Huh-7-vector cells (2 × 10 [6] per mouse) were injected into the livers of nude mice. [score:1]
Co-transfection of a wildtype or a mutant SLC39A6 3′UTR with miR-192 mimics into HEK-293T cells. [score:1]
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Likewise, the protein expression of ERα was upregulated by inhibiting miR-192-5p expression in T47D/LY6K stable cells (Figure 4E). [score:10]
In addition, to observe whether the inhibition of miR-192-5p expression restored the mRNA expression of ERα, we generated a T47D stable cell line over -expressing human LY6K genes (T47D/LY6K) using G418 selection. [score:9]
Our findings provides a rationale for downregulating miR-192-5p or re -expressing miR-500a-3p as a potential therapeutic strategy for treating tamoxifen resistant patients. [score:6]
To determine whether the reduced expression of ERα was due to direct targeting among miR-29b-3p, miR-29c-5p and miR-192-5p, we cloned luciferase reporter construct ESR1 3′-UTR containing the predicted binding site for each miRNA (Figure 4A and Supplementary Figure S2A). [score:6]
In conclusion, the expression of miR-192-5p is up-regulated because of increased LY6K in ERα -positive and LY6K -negative breast cancer. [score:6]
Moreover, compared to the negative miRNA inhibitor (NC), inhibition of the miR-192-5p expression made T47D/LY6K cells more susceptible to tamoxifen (Figure 6A). [score:6]
T47D/LY6K cells were seeded and transfected with miR-192-5p inhibitor or a negative control inhibitor at a final concentration of 30 nM using siPORT™ neoTX™ transfection Agent (Ambion, USA). [score:5]
Mimic, miR-192-5p mimic treated cell; inhibitor, miR-192 inhibitor treated cell. [score:5]
Increased expression of miR-192-5p leads to decreased ERα expression, which is one of the problems that lead to tamoxifen resistance in ERα -positive cancer. [score:5]
These results provide clues that not only the molecular mechanism of LY6K and ERα in breast cancer but also the inhibition of miR-192-5p in ERα -positive breast cancer and the overexpression of miR-500a-3p in ERα -negative breast cancer could be effective therapeutic agents. [score:5]
Figure 6(A) Cell viability after transfection with miR -negative control inhibitor (NC) and miR-192-5p inhibitor in stably overexpressing LY6K (T47D/LY6K) cells was measured 3 hours after treatment with 4-OHT in a dose -dependent manner. [score:5]
Consequently, inhibition of miR-192-5p restored ERα mRNA expression. [score:5]
Caspase-3 activity was increased by treatment with the miR-192-5p inhibitor in comparison with the negative miRNA inhibitor (NC) after incubating T47D/LY6K cells with tamoxifen (Figure 6B). [score:5]
In addition, miR-192-5p expression was increased in primary tumor samples treated with tamoxifen (Figure 7), so inhibition of miR-192-5p could be a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer. [score:5]
These results suggested that increasing expression of miR-192-5p could lead to recurrence in ERα -positive breast cancer patients because reduced expression of ERα is one of the causes of tamoxifen resistance. [score:5]
miR-192-5p directly binds ERα 3′UTR and regulates its expression. [score:5]
miR-192-5p induced by LY6K suppresses ERα expression. [score:5]
Although LY6K is not known as a transcriptional factor, transcription of miR-192-5p might be indirectly promoted by ectopic expression of LY6K. [score:4]
The mechanism for miR-192-5p and miR-500a-3p effects on tamoxifen susceptibility through the regulation of target genes in breast cancer. [score:4]
To assess a possible role for the downregulation of ERα in MCF7 and T47D, we transfected either a miR-192-5p mimic (mimic) or a negative control mimic (NC). [score:4]
These findings describe not only the loss of ERα correlated with miR-192-5p, induced by LY6K, in ERα -positive breast cancer but also how upregulation of miR-500a-3p affects tamoxifen -induced cell death in ERα -negative breast cancer. [score:4]
Recently, miR-192-5p was also identified as a potential target for esophageal cancer cells in a study profiling the development of chemotherapy resistance [26]. [score:4]
Having demonstrated the miRNA -dependent reciprocal regulation of LY6K and ERα expression, we further studied whether miR-192-5p and miR-500a-3p are functionally involved in tamoxifen responsiveness in breast cancer. [score:4]
By investigating the molecular mechanism behind the functions of miR-192-5p and miR-500a-3p in the regulation of ERα and LY6K, how miR-192-5p, induced by LY6K, causes tamoxifen resistance by inhibiting ERα expression in ERα -positive breast cancer. [score:4]
Patients with recurrence showed increased miR-192-5p expression (Figure 7B). [score:3]
The mRNA and protein of ERα were significantly reduced by the overexpression of miR-192-5p in both MCF7 and T47D (Figure 4C). [score:3]
Inhibition of miR-192-5p sensitizes resistance to tamoxifen in breast cancer cells. [score:3]
Figure 4(A) Gene structure of ESR1 showing the predicted target site of miR-192-5p in its 3′-UTR. [score:3]
Taken together, miR-192-5p, induced by LY6K, repressed the level of ERα expression. [score:3]
We confirmed the miR-192 expression using qRT-PCR after treating mimic (Supplementary Figure S3A). [score:3]
The apoptotic cells was reduced by ectopic miR-192-5p in T47D cells (Figure 6C), suggesting that the miR-192-5p suppressed tamoxifen -induced apoptosis. [score:3]
Since the inhibition of miR-192-5p in T47D/LY6K affected cell viability, we further investigated the effect of tamoxifen -induced apoptosis by inhibiting the activity of miR-192-5p. [score:3]
In addition, we observed miR-192-5p and miR-500a-3p expression in primary breast tumors treated with tamoxifen. [score:3]
T47D/LY6K cells were transfected with miR-192-5p inhibitor or negative control then treated with 4-OHT. [score:3]
By using T47D/LY6K cells, we repressed the expression of miR-192-5p and confirmed the level of miR-192-5p by qRT-PCR (Supplementary Figure S3B). [score:3]
In conclusion, the results of the dual luciferase assay confirmed that miR-192-5p directly targets ESR1. [score:3]
The expression of miR-192-5p is transcriptionally activated by TGF-beta, which well known as growth factor stimulated by MMPs [24, 25]. [score:3]
From these results, miR-192-5p appears to regulate resistance to tamoxifen through cell viability along with cell apoptosis. [score:2]
In conclusion, we showed for the first time that the involvement of miR-192-5p and miR-500a-3p regulates the mechanism for the interaction between ERα and LY6K and is related to tamoxifen responsiveness in breast cancer. [score:2]
miR-192-5p and miR-500a-3p involved in LY6K and ERα are related to tamoxifen resistance in breast cancer patients. [score:1]
The seed sequence of miR-29b-3p, miR-29c-5p and miR-192-5p on human ERα 3′UTR was mutated by with a PCR -based approach. [score:1]
miR-192-5p and miR-500a-3p mediates tamoxifen sensitivity in breast cancer. [score:1]
Each primary miRNA produces mature miRNAs (Pri-miR-29a/b1: miR-29b, Pri-miR29b2/c: miR-29b and miR-29c, Pri-miR-194-2/192: miR-192-5p and miR-194, Pri-miR-194-1: miR-194, Pri-miR-34a: miR-34a, Pri-miR-500a: miR-500a-5p or-3p). [score:1]
500 ng of total RNA was reverse transcribed with the TaqMan [®] MicroRNA Reverse Transcription Kit (Applied Biosystems) for has-miR-192-5p or has-miR-500a-3p detection. [score:1]
Here, we showed that miR-192-5p, induced by LY6K, and miR-500a-3, induced by ERα, were selected through microRNA microarray (Figure 3 and Supplementary Figure S1). [score:1]
We observed that miR-192-5p was related to tamoxifen resistance through cell viability and apoptosis in breast cancer cells (Figure 6). [score:1]
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The diagram shows the reduction of the potential mRNA targets for miR-192 achieved by integrating miRNA and gene expression data: first, miR-192 is connected with its targets predicted by the Microcosm database; second, miR-192 is connected with its targets predicted by Microcosm and also found deregulated during activation of human HSCs (p < 0.01) and finally, the functionally relevant miR-192 targets based on significant negative correlation between miR-192 and its predicted targets and the MicroCosm prediction value is shown (B) Histogram representing differentially expressed miRNAs according to the number of deregulated target genes assigned by miRNA-gene integration analysis (p < 0.01). [score:19]
MiR-21 and miR-100 inhibition causes an increase of the expression levels of their target genes while miR-192 overexpression decreases target gene expression levels (B) In vitro modulation of miR-21, miR-100 and miR-192 expression result in a reduction of HSC activation. [score:15]
In the present study, we also provide evidence for the role of miR-192 in the regulation of HSC activation by showing that overexpression of miR-192 suppresses TGFβ1 -induced up-regulation of classical activation genes, i. e. [score:9]
As expected, by increasing the expression levels of miR-192 we observed a significant reduction in the expression of its target genes, PLAU and COL5A1, as well as a modest but significant reduction of the activation marker LOX and an increase in SPARCL1, a novel quiescence marker identified in the gene expression array. [score:9]
Primer sequences used are listed in Supplementary Table 3. In vitro modulation of miRNA expression in human HSCs (LX2)In order to validate relevant miRNA-mRNA interactions resulting from the integrative analysis, miR-21 and miR-100 expression were knocked down and miR-192 was over-expressed in a human HSC cell line (LX2) (kindly provided by Dr. [score:7]
Importantly, miR-192 overexpression clearly inhibited the TGFβ1 -induced activation of qHSCs as measured by the suppression of Acta2, Col1a1 and Lox expression, three key early activation markers in HSCs (Fig. 6C). [score:7]
Among all miRNAs included in this panel we have shown that miR-192 is down-regulated both during in vivo and in vitro activation of qHSCs and that overexpression of miR-192 exerts a functional role during the activation program by reducing activation, migration and proliferation of HSCs. [score:6]
Reduction of miR-21 and miR-100 expression and up-regulation of miR-192 in LX2 cells was achieved by transfecting miR-21 antagomir (50 nM), miR-100 antagomir (50 nM) or miR-192 mimic (50 nM), respectively (n = 3). [score:6]
Interestingly, miR-192 expression in HSCs was clearly reduced during fibrogenesis at very early time points in both animal mo dels indicating that down-regulation of miR-192 in HSCs might be an early event during HSC activation and fibrogenesis (Fig. 6A). [score:6]
In vitro modulation of miR-192 in activated human HSCsMiR-192 has a high number of predicted target genes (n = 28) in qHSCs, displays a significant reduction in expression between healthy and cirrhotic human liver tissue and it has not been previously reported to be associated with HSC or liver fibrosis. [score:5]
Our results indicate that qHSCs are the major source of miR-192 expression in the healthy liver and that the expression of this miRNA in HSCs is lost upon culture -induced and in vivo activation (Fig. 6B). [score:5]
Primer sequences used are listed in Supplementary Table 3. In order to validate relevant miRNA-mRNA interactions resulting from the integrative analysis, miR-21 and miR-100 expression were knocked down and miR-192 was over-expressed in a human HSC cell line (LX2) (kindly provided by Dr. [score:5]
MiR-192 was found significantly down regulated (relative expression of 0.68, fold change = −1.47) in cirrhotic livers compared to healthy livers indicating that this miRNA, which we have identified as highly expressed in qHSC by the miRNA array, could also be detected in healthy tissue (Fig. 4A). [score:5]
Mir-192 expression is shown relative to whole liver (C) Effect of miR-192 over -expression on cell activation, migration and proliferation in primary mouse HSCs. [score:5]
The selection was based on its enrichment in quiescent HSC and healthy liver tissue, the high number of predicted targets, the loss of expression in cirrhotic patients as well as the novelty of miR-192 in the context of liver fibrosis. [score:5]
MiR-192 is highly expressed in qHSCs and might play a functional role in suppressing HSC activation. [score:4]
MiR-192 has a high number of predicted target genes (n = 28) in qHSCs, displays a significant reduction in expression between healthy and cirrhotic human liver tissue and it has not been previously reported to be associated with HSC or liver fibrosis. [score:4]
Expression and function of miR-192 in primary mouse HSCs. [score:3]
In order to identify other cells producing miR-192 in the healthy liver, miR-192 expression was assessed in freshly isolated hepatic cell populations (i. e. hepatocytes, KCs, LSECs and qHSC) from healthy mouse livers. [score:3]
Next, to understand the dynamics of miR-192 expression during HSC activation, we used HSCs isolated from mouse livers. [score:3]
Particularly, these findings indicate that miR-192 can actively promote a quiescent phenotype in fibrogenic conditions and suggest potential therapeutic value for the modulation of miR-192 expression. [score:3]
Additionally, we find that miR-192 overexpression significantly repressed the proliferation and migratory potential of primary mouse HSCs, both key functional properties acquired during HSC activation. [score:3]
In vitro modulation of miRNA-21, miRNA-100 and miRNA-192 expression in LX2 cells. [score:3]
LX2 cells were transfected with 50 nM of mirVana [TM] miRNA Inhibitor for miR-21 and miR-100 and mirVana [TM] miRNA mimic for miR-192 (Life Technologies) using JetPRIME® (PolyPlus, Illkirch, France) according to the manufacturer’s recommendations. [score:3]
Other miRNAs such as miR-192, miR-139-5p, miR-483-5p, miR-142-3p, miR-142-5p, or miR-375 have not been previously described to be expressed in HSCs. [score:3]
Moreover, miR-192 mimics reduced the expression of key activation markers in a human HSC cell line. [score:3]
Mir-192 expression levels were assessed in HSCs isolated from control mice, mice treated with CCl [4] and from mice after BDL- or sham-operation at indicated time points after treatment or surgery. [score:2]
As found in human, HSCs derived from healthy mice presented significant higher levels of miR-192 compared to the HSCs isolated from fibrotic mice and its expression was rapidly reduced upon induction of fibrosis in vivo. [score:2]
Consistent with this result, PDGF -induced migration of mouse HSCs was reduced by miR-192 transfection (Fig. 6C). [score:1]
Additionally, we aimed to explore whether the level of miR-192 functionally contributed to the reduction of HSC activation (Fig. 6C). [score:1]
For those reasons, we selected miR-192 for further functional characterization by modulating its expression in human and mouse HSCs (Figs 5 and 6). [score:1]
Freshly isolated, primary mouse HSCs were seeded at a density of 15.000 cells/cm2 and transfected with miR-192 or control mimic 24 h after plating. [score:1]
Cell proliferation was assessed in mouse HSCs after 24 hours mimic miR-192 transfection (Life Technologies). [score:1]
Finally, the effect of overexpressing miR-192 on cell activation was evaluated by exposing freshly isolated mice HSCs to TGFβ1 (10 ng/mL) or solvent for 48 hours. [score:1]
In vitro modulation of miR-192 in activated human HSCs. [score:1]
Although the modulation of individual activation markers by miR-192 mimic may be modest, we provide evidence that miR-192 has a functional effect on HSCs. [score:1]
Next we tested if miR-192 was able to repress functional activation features. [score:1]
Taken together these results suggest that miR-192 is a qHSC enriched miRNA in the liver with a functional role during HSC activation. [score:1]
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Among 80 genes which were significantly altered and predicted as target genes for miR-192 by databases miRanda and TargetScan, 56 genes were up-regulated while 24 genes were down-regulated post-challenge. [score:11]
Among the genes we have previously reported to be altered following allergen inhalation challenge [2], predicted target genes of miR-192 were largely up-regulated suggesting the inhibitory role of miR-192 on their expression. [score:10]
In the canonical pathway mo deling in our results for the up-regulated target genes for miR-192, cell cycle regulation and response to DNA damage was one of the top-listed pathways, suggesting that miR-192 mediates cell cycle regulation of blood cells in response to allergen challenge. [score:8]
Signalling pathways and cellular processes for target genes, which were reportedly up-regulated in post-allergen challenge and predicted to be targeted by miR-192, were defined through GeneGo MetaCore databases: Functional Enrichment by Ontology and Canonical Pathway Mo deling. [score:8]
Target genes for miR-192 were predicted using databases, miRanda and TargetScan to list the targets identified by both. [score:7]
A study comparing miRNA expression in a wide range of haematological cell lines showed that miR-192 was up-regulated in activated B cells [18]. [score:6]
Genes up-regulated in allergen inhalation challenge and targeted by miR-192. [score:6]
MiR-192 was down-regulated in both comparisons (Figure 2A), that is, miR-192 was significantly under-expressed in asthmatics (pre-challenge) compared to HCs and decreased following allergen inhalation challenge. [score:5]
In order to determine whether miR-192 expression was associated with certain cell-type frequencies, a multiple regression of miR-192 expression onto the cell-type frequencies was performed for each group (HC, pre and post) independently. [score:5]
MiR-192 expression at the same frequency of granulocytes is similar between HCs and asthmatics (pre- and post-challenge), however, the mean miR-192 expression was significantly (p=0.012) higher in HCs than in asthmatics (pre-challenge) for the same frequency of PBMCs independent of the frequency of granulocytes (Figure 2B). [score:5]
The regression coefficient for PBMCs in healthy individuals (i. e. miR-192 expression in PBMCs in HC) was significantly (p=0.036) higher than the regression coefficient for PBMCs in asthmatics at pre-challenge (i. e. miR-192 expression in PBMCs in asthmatics at pre-challenge) (Figure 3B). [score:5]
To clarify the suggestive mechanisms of miR-192 in allergen inhalation challenge, genes targeted by miR-192 were retrieved from the list of differentially expressed genes between pre- and 2 hour post-allergen challenge, which Kam et al. reported in their manuscript [2]. [score:5]
Then the target genes for miR-192 were selected out of 1595 differentially expressed genes, which were identified post-allergen inhalation challenge at an FDR of 5% by Kam et al. [2]. [score:5]
The cell cycle checkpoint control genes, p53 and p21 were overexpressed in cells with overexpressed miR-192 in vitro using human cell lines [9]. [score:5]
Although the origin of the miRNA needs to be clarified, our data showing down-regulated miR-192 in the blood after allergen inhalation challenge may indicate similar TGF-β derived mechanisms. [score:4]
The normalized relative miR-192 expression quantified using RT-qPCR was also regressed onto the relative cell-type frequencies of granulocytes and PBMCs for HC and pre-challenge in separate linear mo dels. [score:3]
The regression coefficients representing the mean miR-192 expression for granulocytes and PBMCs were extracted for each group (Additional file 1: Figure S2). [score:3]
Figure 3 Technical validation of miR-192 expression in whole blood and PBMCs. [score:3]
Although Figure 2B shows that miR-192 expression in PBMCs decreases post-challenge which is also seen in whole blood (Figure 2A), this change was not significant. [score:3]
This may suggest that the decrease in miR-192 seen in whole blood (Figure 2A) may be due to a decrease in miR-192 expression in PBMCs independent of changes in the frequency of granulocytes. [score:3]
The normalized relative miR-192 expression quantified using RT-qPCR specific to PBMCs was also validated. [score:3]
B. Cell-specific miR-192 expression in granulocytes (gray bar) and PBMCs (white bar) comparing healthy control (HC) and asthmatics pre and post-challenge (Pre, Post). [score:3]
In addition, as a biomarker in peripheral blood, miR-192 has been reported to decrease in systemic lupus erythematosus, a systemic autoimmune disease inducing inflammatory responses [11]. [score:3]
Interestingly, miR-192 expression is also reportedly decreased in response to TGF-β and loss of miR-192 correlates with tubulointerstitial fibrosis and reduction in renal function in renal biopsies from patients with established diabetic nephropathy [12]. [score:3]
One common miRNA, miR-192, was significantly expressed in both comparisons; HCs vs. [score:3]
We utilized this approach to analyse cell-specific analysis for miR-192 expression in granulocytes and PBMCs. [score:3]
Cell specific expression of miR-192 was associated with peripheral blood mononuclear cells (PBMCs). [score:3]
Since the mechanism of miR-192 has not been elucidated in allergic airway diseases, further studies are needed to clarify these mechanisms. [score:3]
Cell-specific statistical deconvolution attributed miR-192 expression in whole blood to PBMCs. [score:3]
A. MiR-192 expression in whole blood. [score:2]
MiR-192 has been studied in various conditions including cancer and autoimmune diseases. [score:2]
MiR-192 expression in peripheral blood mononuclear cells (PBMCs). [score:2]
post-challenge, showing that miR-192 was significantly under-expressed in asthmatics compared to HCs and decreased in post-challenge at an FDR of 1%. [score:2]
Several reports showed that miR-192 affects cellular proliferation through the p53 pathway, which regulates cell cycle. [score:2]
Since it is possible to achieve statistical significance with smaller treatment effects in a paired study design, using an unpaired test statistic may explain why the reduction of miR-192 expression in PBMCs post-challenge compared to pre-challenge was not statistically significant (Figure 2B). [score:2]
A. MiR-192 expression quantified using RT-qPCR in whole blood. [score:2]
Given that the cigarette smoke exposure induces airway inflammation and cellular stress such as oxidative stress, this report supports our findings that miR-192 is regulating the response to miRNAs to environmental exposure inducing airway inflammation. [score:2]
B. MiR-192 expression in PBMCs comparing healthy control (HC) and asthmatics (pre-challenge). [score:2]
Figure 2 MiR-192 expression in whole blood and in peripheral blood mononuclear cells (PBMCs). [score:2]
In the other study investigating the response of miRNA to environment, exposure to cigarette smoke decreased miR-192 expression in the lung in animal experimental mo del [10]. [score:1]
The difference of miR-192 levels is suggested to be derived from PBMCs in our data, suggesting that further studies on the subtype of lymphocytes and monocytes will help reveal the mechanisms of miRNA in asthma and asthmatic responses as well. [score:1]
Change in miR-192 levels may be implicated in asthma mechanisms. [score:1]
Among them, changes in miR-192 level may be involved in asthma mechanisms. [score:1]
As shown in the other top-listed pathway in the canonical pathway mo deling in our data, miR-192 was suggested to mediate the immune response following allergen inhalation. [score:1]
Collectively, a further study using a different cohort consisting of a large sample size is needed to validate the decrease in miR-192 levels in asthmatics after allergen inhalation challenge. [score:1]
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[+] score: 110
By overlapping the list of downregulated genes and targets of miR-192, we identified 123 potential targets of miR-192 in HD (Supplementary Fig.   S4D and Table  S3). [score:8]
Particularly, our data showed that the overexpression of miR-192 increased the expressions of endodermal markers GATA4/ 6, while knockdown of miR-192 increased the expression of mesodermal marker PAX2. [score:8]
However, when miR-192-5p and miR-192-3p inhibitors were transfected from HD 6–12, we observed an upregulation of the MGAT4C transcript levels at HD 12 (Fig.   4G). [score:6]
To predict targets of miR-192 in a more deterministic manner, we applied bioinformatics analysis by combining published transcriptional datasets and the in silico target prediction (Fig.   4A). [score:5]
In addition to this, we also examined the expression change of MGAT4C upon disturbance of miR-192 expression. [score:5]
We examined the expression changes of lineage-specific genes while modulating miR-192 expression during HD. [score:5]
Since CALN1 is a human brain-specific gene, whereas MGAT4C is normally expressed in mesodermal tissues like the kidney and ADCYAP1R1 encodes the receptor for peptide signals in response to stress in the brain 45– 47, we reasoned that miR-192 may promote HD via repressing genes normally expressed in the other two germ layer-derived lineages. [score:5]
When H1 cells were transfected with miR-192-5p/ 3p mimics from HD 0–6, GATA4 and GATA6—which are expressed during definitive endoderm differentiation [48]—were elevated with the overexpression of miR-192-5p/ 3p (Fig.   5A). [score:5]
The qPCR analysis confirmed that miR-192-5p/ 3p were only upregulated during HD (Fig.   4B and Supplementary Fig.   S4A). [score:4]
First, we confirmed that miR-192 and miR-372-3p directly repressed their downstream targets. [score:4]
Given that both microarray and qPCR analysis detected a significant downregulation of MGAT4C, we further examined the molecular effects of miR-192 on this gene. [score:4]
Given that endoderm and mesoderm share the same progenitors, perhaps the upregulation of miR-192 potentially affects the segregation of endodermal and mesodermal cell fate, leading to an increase in the formation of hepatic endoderm at the expense of mesodermal formation [50]. [score:4]
Inhibitors of negative control, miR-192-3p, miR-192-5p, and miR-372-3p were purchased from Thermo Fisher Scientific. [score:3]
With further filtration by miRWalk, in which the interactions between miRNAs and mRNAs could be predicted by different online tools, common targets of miR-192-3p and miR-192-5p were identified (Supplementary Fig.   S4C and Table  S3). [score:3]
Mimics of non -targeting control, miR-192-3p, miR-192-5p, and miR-372-3p miRNAs were purchased from GenePharma. [score:3]
Taken together, we concluded that miR-192 is likely a key miRNA that promotes endodermal hepatic differentiation while inhibiting the formation of mesoderm. [score:3]
We first sought to determine what the targets of miR-192 in HD. [score:3]
10 pmol synthetic miRNA mimics of specific miRNAs, including miR-192-3p, miR-192-5p, and miR-372-3p or non -targeting control (GenePharma, Shanghai, China), and 200 ng reporter plasmids were co -transfected with 1 μl Lipofectamine 2000 according to the manufacturer’s instructions. [score:3]
The accession projects supporting the prediction of downstream targets of miR-192 are GSE14897 and GSE25744. [score:3]
Based on this atlas, those miRNAs with lineage-specific expressions, such as miR-192 and miR-372-3p, were easily identified. [score:3]
Targets of miR-192 and miR-372-3p in lineage specification were predicted computationally. [score:3]
Conversely, the intermediate mesoderm marker PAX2 and the MM marker HOXD11 were significantly increased upon inhibition of miR-192-5p/ 3p from HD 6–12 (Fig.   5B and Supplementary Fig.   S5), supporting that miR-192-5p/ 3p repress mesodermal differentiation. [score:3]
s showed that miR-192-5p and miR-192-3p mimics could suppress the MGAT4C 3′UTR (Fig.   4E). [score:3]
In this study, we identified miR-192 and miR-372-3p as key miRNAs regulating HD and KD, respectively. [score:2]
To further validate miR-192 and miR-372-3p as key miRNAs, we performed comprehensive experiments to validate their regulatory functions in HD and KD. [score:2]
Next, we determined the regulatory effects of miR-192 on lineage specification. [score:2]
When H1 cells were transfected with miR-192-5p and miR-192-3p mimics from HD 0–6, MGAT4C transcript levels were moderately decreased (Fig.   4F). [score:1]
When H1 cells were transfected with miR-192-5p mimics, ICG analysis showed that the percentage of ICG -positive cells at HD12 was increased substantially (Fig.   5C,D). [score:1]
The newly identified key miRNAs (miR-192-3p/5p and miR-372-3p) are indicated in the dendrograms that they are included. [score:1]
Effects of miR-192 on hepatocyte differentiation. [score:1]
By ranking the fold-change of lineage-specific miRNAs, we found that both miR-192-5p and miR-192-3p ranked the highest among the HD 6–10 subcluster (Fig.   3B and Supplementary Table  S2), increasing our suspicion that they were candidate key miRNAs. [score:1]
To demonstrate the effects of miR-192 on HD, we also determined the functional characteristics of HD 12 cells when modulating the expression of miR-192. [score:1]
These validations prove that miR-192 and miR-372-3p are truly key miRNAs. [score:1]
A negative correlation between miR-192-5p/ 3p and CALN1/ MGAT4C/ ADCYAP1R1 was observed (Fig.   4D and Supplementary Fig.   S4F). [score:1]
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7
[+] score: 91
Other miRNAs from this paper: mmu-mir-192
Furthermore, inhibition of miR-192-5p also suppressed VAN induced AKI, the cell cycle arrest was also reversed by miR-192-5p inhibitors, which was supported by the finding that miR-192 can enhance cell cycle arrest 41. [score:7]
However, the role of miR-192-5p in apoptosis is dependent on the cell types/stress factors, miR192-5p as a potential new therapeutic target for other diseases could be further explored. [score:5]
Although miR-192-5p might suppress apoptosis in A549 cells, inhibition of it did not alleviate apoptosis in the miR-192-5p non-responsive H1299 cells 23. [score:5]
MiR-192-5p expression was further confirmed by Northern blot analyses, at day 3 and 7 after VAN treatment, it was markedly downregulated in p53- KO mice than in p53-WT mice (Fig. 4C and D). [score:5]
In current study, we also demonstrated that inhibition of p53 significantly suppressed miR-192-5p in vitro and vivo. [score:5]
Real time PCR showed that VAN significantly induced miR-192-5p expression that was suppressed by pifithrin-α treatment (Fig. 7A). [score:5]
To the date, we identified p53 promoted apoptosis by upregulation of miR-192-5p in HK-2 cells, revealing the involvement of this mechanism not only in HK-2 cells, but also in p53 knockout mice. [score:5]
However, miR-192-5p suppresses apoptosis by targeting Bim in esophageal aquamous cell caicinoma 40. [score:5]
In HK-2 cells and the mouse mo del, inhibition of p53 ameliorated VAN induced AKI through miR192-5p regulation. [score:4]
MiR192-5p expression is suppressed in p53 KO mice. [score:4]
Moreover, we have identified that miR-192-5p was regulated through p53 in vivo and vitro, and further revealed that p53 induced renal cell apoptosis via directly up regulation of miR-192-5p. [score:4]
To further confirm whether p53 induce the expression of miR-192-5p, pifithrin-α was used in current study. [score:3]
Jin et al. reported that miR-192-5p provoked apoptosis by suppression of XIAP in tumor cell lines 23 39. [score:3]
Inhibition of miR-192-5p ameliorated renal dysfunction, renal injury in VAN nephrotoxic AKI mice. [score:3]
As shown in Fig. 7C and D, VAN induced more apoptosis rate and caspase activity in HK-2 cells were inhibited by anti-miR-192-5p. [score:3]
In our study, we demonstrated that antagonizing VAN induced miR-192-5p by miRNA inhibitors decreased apoptosis in HK-2 cells. [score:3]
These data suggest that miR192-5p may act as an apoptosis promoter, and thus may be considered as a potential therapeutic target for VAN induced AKI. [score:2]
To further reveal the in depth molecular mechanism of p53 for regulation of apoptosis, we focus on the miR-192-5p. [score:2]
To further investigate the mechanisms how inhibition of p53 ameliorates VAN induced AKI, we focused on the miR-192-5p. [score:1]
VAN induced miR-192-5p was blocked in p53- KO mice. [score:1]
In scrambled mice, the tubular damage score was 3.7 after vancomycin AKI, whereas the score was markedly decreased to 1.5 after vancomycin AKI for anti–miR-192-5p tissues (Fig. 8D). [score:1]
To assess the role of miR-192-5p in the pathogenesis of VAN nephrotoxic AKI, male C57BL/6 mice were injected with LNA -modified antisense oligonucleotide of miR-192-5p (anti–miR-192-5p) or LNA -modified oligonucleotide of the scrambled sequence (scrambled), levels of BUN and serum creatinine were similarly low in these mice, indicating normal renal function. [score:1]
p53 induced miR-192-5p for apoptosis during VAN treatment. [score:1]
In addition, the experiment on role of miR-192-5p, male C57BL/6 mice were injected by tail vein with or without 20 mg/kg LNA -modified antisense oligonucleotide of miR-192-5p (anti–miR-192-5p) or LNA -modified oligonucleotide of scrambled sequence (scrambled) for 7 days. [score:1]
HK-2 cells were treated with 4 mm/L VAN in presence or absence of 20 μM pifithrin-α for 24 h, or transfected with 100 nmol/L LNA -modified antisense oligonucleotide of miR-192-5p (anti–miR-192-5p) or LNA -modified oligonucleotide of the scrambled sequence (scrambled). [score:1]
Recent studies demonstrated that miR-192-5p mediated apoptosis in a few of tumor cell line 23. [score:1]
Male C57BL/6 mice were (A–D) injected with 400 mg/kg (n = 8) with or without 20 mg/kg LNA -modified antisense oligonucleotide of miR-192-5p (anti–miR-192-5p) or LNA -modified oligonucleotide of scrambled sequence (scrambled) for 7days of examination. [score:1]
How to cite this article: Chen, J. et al. p53 activates miR-192-5p to mediate vancomycin induced AKI. [score:1]
Blockade of miR-192-5p reduces VAN induced apoptosis in HK-2 cells. [score:1]
Whole tissue lysate was analyzed for miR192–5p and U6 by Real-time PCR or Northern blot. [score:1]
Recent study reported that p53 could physically interact with the promoter region of miR-192-5p 42. [score:1]
At day 7 of VAN treatment, scrambled mice developed moderate renal failure, with 102.5 mg/dl BUN and 0.43 mg/dl serum creatinine, whereas anti–miR-192-5p mice had 65.9 mg/dl BUN and 0.22 mg/dl serum creatinine (Fig. 8A and B). [score:1]
For Pifithrin-a treatment, HK-2 cells were treated with or without Pifithrin-a (20 μM) or vancomycin (4 mm/L) for 24 h. For transfection experiment, transfection of miR-192-5p analog (100 nM) or negative control (miR-neg; Sigma) were used. [score:1]
Blockade of miR-192-5p reduced VAN induced AKI. [score:1]
As shown in Supplemental Figure 4, VAN induced the cell cycle arrest, which was reduced in anti–miR-192-5p tissues. [score:1]
Histologic analysis confirmed the VAN induced kidney tissue damage, which was significantly ameliorated in anti–miR-192-5p mice (Fig. 8C). [score:1]
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8
[+] score: 77
Furthermore, we found a significant upregulation of miR-19, miR-192, miR-194, and miR-215 in the tumor compartment of the lung metastases and a significant downregulation of the same miRNAs in the liver metastases. [score:7]
Downregulation of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (p = 0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the normal liver tissue was significantly associated with poor survival, suggesting oncosuppressive effects of these miRNAs. [score:6]
miR-192 showed a 4-fold upregulation in the tumor compartment of the liver metastases (p < 0.0001) and a 5-fold upregulation in the tumor compartment of the lung metastases (p < 0.0001) compared to the stroma. [score:6]
miR-192 and miR-215 have been shown to be upregulated by p53, a tumor suppressor. [score:6]
These contradictory results could be explained by the 1000-fold and 300-fold downregulation of miR-192, miR-194, and miR-215 in the host tissue of the lung compared to the liver, thus resulting in a relative upregulation in the tumor and stroma compartment. [score:6]
In the host tissue of the liver metastases, we identified several miRNAs with significant correlations between expression and survival: downregulation of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) was associated significantly with poor survival (Table 4). [score:6]
miR-192 and -215 have been found to be downregulated in primary colorectal cancers [16]. [score:4]
Our results show a downregulation of miR-192, miR-194, and miR-215 in the tumor and the tumor -associated stromal compartment of the liver metastases. [score:4]
Noteworthy, miR-215, miR-194, and miR-192 showed a more than 100-fold upregulation in the normal liver tissue compared to the normal lung tissue. [score:3]
miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and miR-199-5 a 12.5-fold downregulation in the liver metastases compared to the lung metastases. [score:3]
In contrast, miR-192 was significantly downregulated in the tumor and the stroma compartment of the liver metastases compared to normal liver tissue (p < 0.0001). [score:3]
Especially miR-192, miR-194, and miR-215 were downregulated up to 350 times in the lung metastases compared to the liver metastases. [score:3]
miR-192, -194, and -215 are induced by p53, a well-known tumor suppressor, and influence cell proliferation through the induction of cell cycle arrest. [score:3]
Only three miRNAs, miR-127, miR-192, and miR-215, showed a significant expression difference (>2-fold) between all three compartments in both liver and lung metastases (Tables S1 and S2). [score:3]
miR-125 and miR-199-5 showed a 2-fold; miR-19 and miR-127 showed a 4-fold; miR-215 showed a 100-fold; miR-194 showed a 150-fold; and miR-192 showed a 300-fold upregulation in the normal liver tissue compared to the normal lung tissue. [score:3]
Boni V. Bitarte N. Cristobal I. Zarate R. Rodriguez J. Maiello E. Garcia-Foncillas J. Bandres E. miR-192/miR-215 Influence 5-Fluorouracil Resistance through Cell Cycle-Mediated Mechanisms Complementary to Its Post-transcriptional Thymidilate Synthase Regulation Mol. [score:2]
Song B. Wang Y. Kudo K. Gavin E. J. Xi Y. Ju J. miR-192 Regulates Dihydrofolate Reductase and Cellular Proliferation through the p53-microRNA Circuit Clin. [score:2]
Georges S. A. Biery M. C. Kim S. Schelter J. M. Guo J. Chang A. N. Jackson A. L. Carleton M. O. Linsley P. S. Cleary M. A. Coordinated Regulation of Cell Cycle Transcripts by p53-Inducible microRNAs, miR-192 and miR-215 Cancer Res. [score:2]
Compared to the normal tissue, miR-192 showed a significant upregulation in the tumor and the stroma of the lung metastases compared to normal lung tissue (tumor: p < 0.0001; stroma p = 0.0012). [score:2]
The final selection of miRNAs for further analysis consisted of 11 miRNAs: miR-19b, miR-21, miR-125b, miR-127-3p, miR-145, miR-192, miR-194, miR-199a-3p, miR-199a-5p, miR-215, and miR-429. [score:1]
The miRNAs miR-192 and miR-194 are collocated on the miR-192/miR-194-2 cluster on chromosome 11 (11q13.1). [score:1]
miR-192, -194 and -215 are located in the miR-215/miR-194-1 cluster on chromosome 1 (1q41) and the miR-192/miR-194-2 cluster on chromosome 11 (11q13.1). [score:1]
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9
[+] score: 77
miR192-5p expression inhibited HUVEC growth significantly. [score:5]
miR-192-5p overexpression inhibits EC growth. [score:5]
miR-192-5p expression decreased the mRNA levels of two predicted targets, TMPO and CDC25A (Fig. 5A), that were also down-modulated in H [2]O [2] treated cells (Dataset S3). [score:5]
miRNA/target interactions identify miR-192-5p as a hub of endothelial cell response to H [2]O [2]To analyze miRNA expression changes induced by EC exposure to oxidative stress, RNAs derived from HUVEC treated with H [2]O [2] for 16 hrs were analyzed by small RNA-sequencing. [score:5]
Indeed, in keeping with previous observations in cancer cells [30- 32], miR-192-5p activation was p53 -dependent; its expression, in turn, increased the levels of p53-targets, leading to EC growth arrest and death. [score:5]
Enrichment analysis performed with ClueGO on miR-192-5p targets that showed a significant down regulation at both time points in rRNA -depleted RNA-sequencing data. [score:4]
Conversely, miR-192-5p, miR-30a-5p, miR-381-3p, miR-769-5p and let7i-5p were significantly up-regulated, both at 16 and 36 hrs of H [2]O [2] treatment (Fig. 4A and supplementary Fig. S7 in linear scale). [score:4]
miR-192-5p expression has been shown to activate p53 pathway in cancer cells [30- 33]. [score:3]
Interestingly, gene ontology analysis of miR-192-5p targets identified p53-related categories, such as cell cycle and DNA damage/stress response. [score:3]
miRNA/target interactions identify miR-192-5p as a hub of endothelial cell response to H [2]O [2]. [score:3]
Fig. 4B identified miR-192-5p as a hub of miRNA/target interactions in EC response to H [2]O [2]. [score:3]
Accordingly, gene ontology analysis of potential miR-192-5p targets displayed an enrichment in terms related to cell cycle, DNA damage/stress response and microtubules (Fig. 4C). [score:3]
To further validate the relevance of miR-192-5p role in EC growth, we tested the effect of miR-192-5p overexpression in the absence of oxidative stress. [score:3]
Incubation of HUVEC with 0.25 mM BCNU for 2 h increased miR-192-5p levels and this phenomenon was inhibited by preincubation with 10 mM NAC (Fig. S8). [score:3]
miR-192-5p has been described to be a p53 transcriptional target in a variety of cancer cells [30- 32]. [score:3]
Bioinformatic analysis of the interactions between the identified miRNAs and their modulated predicted targets, indicated miR-192-5p as a potential hub of the EC response to H [2]O [2]. [score:3]
Fig. 6B shows that, indeed, p53 knock-down prevented miR-192-5p induction in H [2]O [2] -treated HUVEC. [score:2]
miR-192-5p increase in ischemic muscles. [score:1]
We found that miR-192-5p levels were increased in ischemic muscles of CLI affected patients. [score:1]
Figure 8 shows that miR-192-5p levels were significantly increased in ischemic muscles. [score:1]
However, miR-192-5p precursor transcripts were undetectable by small RNA-sequencing in HUVEC, escaping our analysis. [score:1]
Increased miR-192-5p levels in ischemic muscles. [score:1]
The anti-proliferative and pro-apoptotic activity of miR-192-5p relates with the poor regenerative and cell death milieu observed in the muscles of CLI patients [10]. [score:1]
Accordingly, evidence of a p53-miR-192-5p positive feed-back loop has been found also in multiple myeloma as well as in colon, breast, lung and ovary cancer cell lines [30- 33, 61]. [score:1]
In keeping with these findings, miR-192-5p dramatically decreased HUVEC growth, inducing cell death (Fig. 5B). [score:1]
On the other side, in the qPCR-array study [19] miR-192-5p was induced by H [2]O [2] treatment, but not further pursued, miR-16-5p was not modulated, while probes for miR769-5p were not present in the array. [score:1]
HUVEC were transfected with miR-192-5p mimic or control oligonucleotides. [score:1]
HUVEC were transfected with 60 picomoles of a mix of TP53HSS110905/TP53HSS186391/TP53HSS186390 Stealth p53 -RNAi, with 50 picomoles of hsa-miR-192-5p mirVana miRNA mimic (Life Technologies) or with negative control #1 (Life Technologies) using siRNA transfection reagent (Santa Cruz Biotechnology) in 40% confluent HUVECs, according to the manufacturer's manual. [score:1]
Figure 5HUVEC were transfected with miR-192-5p mimic or control oligonucleotides. [score:1]
Another important noncoding player in p53 pathway seems to be miR-192-5p. [score:1]
Thus, our analysis was limited to miRNAs, that are more resistant to degradation [11, 36], and in particular to miR-192-5p, the most significantly modulated miRNA in H [2]O [2] treated ECs. [score:1]
Unfortunately, low patient numerosity precluded miR-192-5p correlation with clinically relevant parameters. [score:1]
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10
[+] score: 75
Among the analyzed microRNAs, the expression level of miR-200c was profoundly downregulated in these patients and negatively correlated with proteinuria, while the level of miR-192 was significantly upregulated and positively correlated with glomerulosclerosis [23]. [score:9]
High salt diet increased the expression level of miR-192 in the TALH, which in turn suppressed Atp1b1 gene expression [45]. [score:7]
Contrasting with common microRNA target areas, miR-192 appeared to target Atp1b1 through the 5′-rather than 3′-untranslated region, although its binding sites were present within both regions [45]. [score:7]
Mechanistically, overexpression of miR-192 in cultured proximal tubular cells suppressed the expression of Zeb1 and 2, opposing TGF-β -mediated epithelial-to-mesenchymal transition (EMT) [30]. [score:7]
Among the microRNAs highly expressed in the kidney [14, 15], several key microRNAs (miR-192, miR-200b, miR-200c, miR-216a, and miR-217) were upregulated in glomerular mesangium of diabetic mouse mo dels (type I (streptozotocin (STZ) -induced) and type2 (db/db)) (vide infra). [score:6]
In vitro, TGF-β -induced miR-192 was shown to increase the gene expression of collagen 1α2 by reducing the expression of two E-box repressors (Zeb1 and Zeb2) that control collagen 1α2 gene activation [16]. [score:5]
Knockdown of miR-192, in vivo with antisense oligonucleotide, upregulated the Atp1b1 protein level in the kidney, causing antidiuresis under high salt dietary condition. [score:5]
Among them, miR-200b and c are regulated by the miR-192 targets—Zeb1/2 through E-boxes in the promoters of their host genes [20, 21]. [score:4]
Its gene expression was reciprocally regulated by aldosterone, potassium and salt as to miR-192 in the kidney [47]. [score:4]
Among them, miR-192 was found to target the Na [+]/K [+]-ATPase β1 subunit gene (Atp1b1). [score:3]
miR-216a and miR-217 are downstream targets of miR-192 through Zeb1/2 mediated mechanisms [17]. [score:3]
Elvira-Matelot et al. have shown that miR-192 expression is strongly reduced in the kidneys of mice treated with salt depletion, potassium load, or chronic aldosterone infusion, whereas its level is not modified by a high salt diet (Figure 4) [47]. [score:3]
The most effective treatment of kidney diseases with antagomirs was demonstrated in the case of miR-192. [score:3]
In individual biopsies, miR-192 expression was inversely correlated with the progression of tubulointerstitial fibrosis and the loss of GFR. [score:3]
The serine-threonine kinase WNK1 is the target of miR-192 when assayed in vitro and ex vivo. [score:2]
Among them, miR-192 showed the greatest change, the level of which was consistently lower in diabetic patients. [score:1]
Anti-miR-192 treatments ameliorated glomerular fibrosis in mouse mo dels of diabetic nephropathy through a concomitant repression of collagen and fibronectin levels in the mesangial cells [61]. [score:1]
In vivo, the miR-192 and Collagen 1α2 levels were substantially increased in the mesangial cells of STZ -induced diabetic mice, as well as of db/db diabetic mice, suggesting a role in glomerular basement membrane thickening (Figure 2A) [16]. [score:1]
In contrast to its role in the glomerular mesangium, miR-192 appears to play a protective role against tubulointerstitial fibrosis in the proximal tubule of diabetic patients [30]. [score:1]
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11
[+] score: 72
Based on our dual-fluorescent protein vector system, we found that hiv1-miR-N367 and hsa-miR192 down regulate the expression of common artificial target mRNAs and the predicted cellular target of hsa-miR192, PABPC4. [score:8]
The 3′-UTR of the human gene PABPC4 contains two conserved sequential “seed region” pairing sites, which are predicted targets of miR192, as determined by TARGETSCAN and other miRNA target prediction algorithms (http://www. [score:7]
hiv1-miR-N367 and hsa-miR192 downregulate common artificial and predicted biological targets as functional orthologs. [score:6]
These assays demonstrated that miR-N367 and miR192 can inhibit the expression of indicator vectors that contain their own and each other's non-fully complementary target sequences. [score:6]
As the native stem–loops of precursor miR192 not only express the mature sequence of miR192 but also express miR192* (http://microrna. [score:5]
The tar(n) sequence is a non-fully complementary target of miR-N367, and the tar(192) sequence is a non-fully complementary target of miR192 (see Figure 6B). [score:5]
The vector pmiR192 was constructed to express miR192 at high levels and is based on our dual-fluorescent reporter vector. [score:3]
The indicator vectors pmiR-N367:4tar(192) and pmiR192:4tar(192) were constructed by the stepwise insertion of four copies of the non-fully complementary miR192 target sequence (tar(192)) into the 3′-UTR of the mCherry gene in pmiR-N367 and pmiR192 using the Bgl II/Hind III and Hind III/EcoR I, respectively. [score:3]
uk/) as a byproduct, the miR30 -based precursor stem-loops were used to exclusively express miR192 [9] (see Figure S2C). [score:3]
Figure S4 Relative expression level determination of miR30, miR423-5p and miR192 using real-time quantitative PCR method. [score:3]
Thus, the reporter assays demonstrate that targets, such as PABPC4, can be negatively regulated by both miR192 and miR-N367. [score:3]
Additionally, some predicted biological targets were used to further test the orthologous functions of hiv1-miR-N367 and hsa-miR192. [score:3]
The miRNA expression vector pmiR192 was constructed by inserting the miR30 precursor stem-loops based artificial pre-miR192 sequences into the EcoR V and Not I sites of. [score:3]
The expression of miR30, miR423-5p and miR192 was compared to mock transfected sample using 2 [–ΔΔCT] method. [score:2]
A. The 3′UTR sequence of DMWD and the predicted pairing site of hsa-miR423-5p; B. The 3′ UTR sequence of C20orf27 and the predicted pairing site of hsa-miR423-5p; C. The 3′ UTR sequence of PABPC4 and the predicted pairing site of hsa-miR192. [score:1]
The artificial pre-miR192 sequences were generated by overlap extension PCR with the following two partially complementary oligonucleotides: 5′-TGAGCGAGCTGTCAATTCCTAGGTCAGTGGTGAAGCCACAGATGCACTGACCTATG-3′ and 5′-ATTGTTATCGCGGCCGCAAAAAATAGGCAGGCTGTCAATTCATAGGTCAGTGCATC-3′. [score:1]
hiv1-miR-N367 and hsa-miR192 act as functional orthologs. [score:1]
In this study, two pairs of functional orthologs, sv40-miR-S1-5p and hsa-miR423-5p as well as hiv-1-miR-N367 and hsa-miR192, were demonstrated to be potential functional orthologs. [score:1]
In addition, one of the HIV-1-encoded miRNAs, hiv1-miR-N367 [6], [8] (also called nef microRNA), contained a seed sequence identical to that of hsa-miR192. [score:1]
0036157.g006 Figure 6 (A) Sequence homology between hiv1-miR-N367 and hsa-miR192 (marked in red). [score:1]
One of the HIV-1-encoded miRNAs, hiv1-miR-N367 [6], [8], contains a seed sequence identical to that of hsa-miR192 (from 2 [nd] to 7 [th] nucleotides), demonstrating its potential as a functional ortholog of hsa-miR192 (see Figure 6A). [score:1]
With our newly constructed dual-fluorescent protein reporter system, we demonstrated that sv40-miR-S1-5p may function as an ortholog of cellular hsa-miR423-5p and that hiv1-miR-N367 may function as an ortholog of cellular hsa-miR192. [score:1]
HIV-1-encoded hiv1-miR-N367 was also found by sequence alignment to contain a seed sequence identical to that of the cellular miRNA hsa-miR192. [score:1]
These results further demonstrate that hiv1-miR-N367, an HIV-1-encoded miRNA, should act as a functional ortholog of the human-derived miRNA hsa-miR192. [score:1]
A. Secondary structure mo del for artificial pre-miR-S1-5p based on stem-loops of miR-30 precursor; B. Secondary structure mo del for artificial pre-miR423-5p based on stem-loops of miR-30 precursor; C. Secondary structure mo del for artificial pre-miR192 based on stem-loops of miR-30 precursor. [score:1]
Therefore, the results identifying the orthologous function of HIV-1 miR-N367 with hsa-miR192 imply that HIV-1 may take advantage of endogenous cellular miRNAs to benefit viral latency in resting primary CD4+ T lymphocytes. [score:1]
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[+] score: 68
The qRT-PCR analysis indicated that 2 miRNAs (miR-21 and miR-133b) were deregulated in both EAC and GC, and 6 miRNAs (up-regulated: miR-194, miR-31, miR-192, and miR-200a; down-regulated: miR-203 and miR-205) in EAC, as compared to BE but not in GC, indicating their potential unique role in EAC. [score:7]
We found that 2 miRNAs (miR-192, and miR-194) were up-regulated and 3 miRNAs (miR-205, miR-203, and miR-31) were down-regulated in BE as compared to NS (Figures 2 and 3). [score:6]
While miR-194, miR-192, and miR-200a were significantly up-regulated in EAC, they also displayed an interesting pattern with disease progression. [score:6]
Our results indicating up-regulation of miR-21, miR-192, and miR-194 are consistent with previous reports on the miRNA expression profile in EAC [12], [25]. [score:6]
Our validation confirmed the up-regulation of miR-194, miR-192, miR-21, and miR-200a, and the down-regulation of miR-203, miR-205, miR-133b, and miR-31 in EAC as compared to NS. [score:6]
We showed the up-regulation of miR-194, miR-192, miR-21, miR-31, and miR-200a (Figure 2, Table 3) and the down-regulation of miR-133b, miR-203, and miR-205 in EAC as compared to BE (Figure 3, Table 3). [score:6]
Of note, the overexpression levels of miR-194, miR-200a and miR-192 were significantly higher in EAC stage I than in advanced stages (P [ANOVA] ≤0.0009, P [II&III] ≤0.003, and P [I&III] ≤0.006), suggesting that these miRNAs may be involved in tumor development rather than tumor progression (Figure 7). [score:4]
Four miRNAs (miR-194, miR-192, miR-31, and miR-200a) were up-regulated in EAC but not in GC (Table 4, Figure 5). [score:4]
Interestingly, the overexpression levels of miR-194, miR-200a, and miR-192 were significantly higher in early EAC stages, suggesting that these miRNAs may be involved in EAC tumor development rather than progression. [score:4]
We found that miR-192, miR-194, miR-31, and miR-21 were significantly up-regulated in BE tissues adjacent to HGD, relative to the isolated BE samples (P<0.05) (Figure 8, Table 5). [score:4]
Our data showed that miR-194, miR-192, miR-21, and miR-31 were up-regulated in BE adjacent to HGD lesions relative to isolated BE samples. [score:4]
The log10 values of fold expression of the 8 miRNAs (miR-192, miR-200a, miR-194, miR-21, miR-203, miR-205, miR-31, and miR-133b) were used for hierarchical clustering. [score:3]
In addition, our data showed that miR-192, miR-194, miR-21, and miR-31 were significantly dysregulated in BE adjacent to HGD relative to isolated BE tissue samples, showing levels similar to those observed in HGD and EAC. [score:2]
The expression of 4 miRNAs (miR-192, miR-194, miR-21, and miR-200a) was evaluated using qRT-PCR in 46 NS, 13 BE, 17 HGD, and 34 EAC tissues. [score:1]
miR-194, miR-192, miR-200a, miR-21, miR-203, miR-205, miR-133b, and miR-31 were selected for validation using 46 normal squamous (NS), 23 Barrett’s esophagus (BE), 17 Barrett’s high grade dysplasia (HGD), 34 EAC, 33 gastric adenocarcinoma (GC), and 45 normal gastric (NG) tissues. [score:1]
The expression levels of the 4 miRNAs (miR-203, miR-194, miR-192, and miR-200a) were evaluated in EAC tissue samples of stages I, II and III by means of qRT-PCR. [score:1]
0064463.g002 Figure 2 The expression of 4 miRNAs (miR-192, miR-194, miR-21, and miR-200a) was evaluated using qRT-PCR in 46 NS, 13 BE, 17 HGD, and 34 EAC tissues. [score:1]
0064463.g007 Figure 7 The expression levels of the 4 miRNAs (miR-203, miR-194, miR-192, and miR-200a) were evaluated in EAC tissue samples of stages I, II and III by means of qRT-PCR. [score:1]
0064463.g005 Figure 5The expression levels of the 6 miRNAs (miR-194, miR-192, miR-203, miR-205, miR-200a, and miR-31) were measured by means of qRT-PCR in 13 BE, 34 EAC, 45 NG, and 33 GC tissue samples. [score:1]
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[+] score: 65
On the other hand, the expression of miR-192 in DN is controversial [32]; most investigations have found that miR-192 expression increases in DN mo dels and in renal cells, but several other studies have reported that miR-192 expression decreases [33]. [score:5]
These studies indicated that the increased expression of miR-192 was correlated to the early stage of DN and the controversy of miR-192 expression may contribute to the different stages of DN. [score:5]
miR-192, miR-194, and miR-215 have been reported to be highly expressed in kidney tissue and play critical roles in kidney development and differentiation [7]. [score:4]
In our study, we found that exposure to high glucose increased the expression of EV miR-192 and miR-215 in HK-2. In addition, we also determined that miR-192 expression was higher in HK-2 EVs compared to the other two miRNAs as we found in urine samples. [score:4]
miR-192 and miR-215 have been shown to be dramatically upregulated and are involved in promoting renal glomerular and tubulointerstitial fibrosis in DN [9]. [score:4]
However, these results differ from the results of previous studies in which no significant differences in exosomal miR-192 expression were found between micro- and normoalbuminuric DM1 patients [30]. [score:3]
Recently, miR-192 and miR-194 were confirmed to be highly expressed in human proximal tubule and mesangial cells and to play key roles in acute kidney injury (AKI) [28]. [score:3]
Furthermore, Saal and Harvey confirmed this expression pattern in rat kidneys and found that miR-192 and miR-194 are enriched in rat kidney cortex tissue relative to medulla tissue [27]. [score:3]
The combination of urinary EV miR-192 and TGF- β1 expression may provide new insight into the pathology of early-stage DN. [score:3]
Recent studies in DN mouse mo dels have demonstrated that increased glomerular miR-192 levels are positively associated with renal TGF- β1 expression [39], and a feedback amplification circuit was detected between these two factors [40]. [score:3]
As shown in Figure 2, UAER positively correlated with miR-192 expression (r = 0.357, P = 0.005). [score:3]
The expression of urinary EV miR-192, miR-194, and miR-215 was increased in T2DM patients with microalbuminuria. [score:3]
We found that exposure to high glucose significantly enhanced EV miR-192 (t = 7.129, P = 0.019), miR-194 (t = 4.008, P = 0.016), and miR-215 (t = 4.806, P = 0.04) expression levels in HK-2 cells (Figure 5). [score:3]
A recent study reported that miR-192 expression is higher in patients at the early stages of DN compared with those at the late stages [34]; however, in this study, they defined late stage as eGFR < 15 mL/min. [score:2]
ROC analysis revealed that miR-192 had an area under the curve (AUC) of 0.802 (95% confidence interval, 0.696–0.907, P < 0.001), which was better than miR-194 with an AUC of 0.703 (95% confidence interval, 0.581–0.826, P = 0.04) and miR-215 with an AUC of 0.757 (95% confidence interval, 0.545–0.869, P < 0.001) in discriminating the normoalbuminuric group from the microalbuminuric group (Figure 3). [score:1]
Further studies are needed to explore the correlation between renal function and miR-192 levels in renal biopsies, blood, and urine at different stages of DN. [score:1]
As we expected, TGF- β1 levels were positively correlated with both miR-192 (r = 0.356, P = 0.005) and miR-215 (r = 0.332, P = 0.010). [score:1]
However, in another study, miR-192 and miR-194 were found to be decreased in the mesangial cells of diabetic mice [10]. [score:1]
In our study, these miRNAs were also detected in urinary EVs, and the relative abundance of miR-192 was significantly higher than those of miR-194 (Z = 7.913, P < 0.001) and miR-215 (Z = 8.405, P < 0.001), which suggests that miR-192 plays a more important role in the DN process, specifically in renal cell communication. [score:1]
miR-192, miR-194, and miR-215 are particularly abundant in the kidneys relative to other organs [7]. [score:1]
These results are consistent with the available literature, which suggests that miR-192 increases in the early stages of DN [33]. [score:1]
miR-215 and miR-194-1 are located on the same chromosome, as are miR-192 and miR-194-2. miR-192 and miR-215 share the same seed sequence, and miR-194-1 and miR-194-2 possess the same mature sequence [8]. [score:1]
Indeed, miR-192 and miR-194 are highly enriched in proximal tubule and mesangial cells [28], and miR-192 and miR-215 have been shown to play roles in mesangial cell hypertrophy and fibrogenesis [9, 42]. [score:1]
In addition, in EVs from HK-2 cells from both the NG and the HG groups, the miR-192 levels were significantly higher than those of miR-194 (t = 3.001, P = 0.03) and miR-215 (t = 2.668, P = 0.043). [score:1]
Levels of miR-192 (Z = 3.777, P < 0.001), miR-194 (Z = 2.210, P = 0.027), and miR-215 (Z = 3.046, P = 0.002) in patients with diabetes with microalbuminuria were higher than those with normoalbuminuria. [score:1]
In previous study miR-192 was found decreased in diabetic glomerulosclerosis patients with albuminuria between 3.5 and 9.7 g/d and eGFR between 87.8 and 5.6 mL/min/1.73 m [2]. [score:1]
As we did not enroll more patients with macroalbuminuria and cannot get biopsy from all patients, we cannot figure out miR-192 decreased at which point. [score:1]
TGF- β1 levels were significantly correlated with miR-192 (r = 0.356, P = 0.005) and miR-215 (r = 0.332, P = 0.010), and no significant correlation was detected between TGF- β1 levels and miR-194 (r = 0.190, P = 0.146) (Figure 4). [score:1]
In EVs from hMCs, no significant differences were found between miR-192 and either miR-194 (t = 1.333, P = 0.212) or miR-215 (t = 1.146, P = 0.278) (Figure 6). [score:1]
As shown in Table 2, miR-192 levels were higher than the levels of miR-194 (Z = 7.913, P < 0.001) and miR-215 (Z = 8.405, P < 0.001) in urinary EVs. [score:1]
We found that urinary EV miR-192 was positively correlated with albuminuria and can distinguish patients with normoalbuminuria from those with microalbuminuria (AUC = 0.802, P < 0.001). [score:1]
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[+] score: 50
Another target of miRNA-192 that showed overlap with known pathways of alcoholic hepatitis is Jak2/Arhgef1 signaling pathway, which is correlated with severity of liver disease [44]. [score:5]
The targets of miRNA-192 and miRNA-30a target were visualized using Cytoscape V2.7. [score:5]
Using target prediction algorithms, we identified the predicted target protein networks of human miRNA-192 and miRNA-30a (Fig.   6a, b). [score:5]
By performing microarray screening on exosomes, we found nine inflammatory miRNAs which were deregulated in sera of chronic alcohol-fed mice compared to controls including upregulated miRNAs: miRNA-192, miRNA-122, miRNA-30a, miRNA-744, miRNA-1246, miRNA 30b and miRNA-130a. [score:4]
Predicted targets of miRNA-192. [score:3]
Based on ROC curve analysis, exosome -associated miRNA-192 can act as an accurate diagnostic test for discrimination of liver disease in the population (AUC = 0.95; p < 0.001) (Fig.   5e, f; Table  3). [score:3]
b Potential targets of miRNA-192. [score:3]
Fig.  6Target prediction for miRNA-30a and miRNA-192. [score:3]
Comparing the miRNA signature of exosomes from alcohol-fed mice with pair-fed mice showed deregulation of nine inflammatory miRNAs including miRNA-122, miRNA-192 and miRNA-30a. [score:2]
However, more data regarding specificity of miRNA-192 and miRNA-30a for alcoholic hepatitis compared to the other types of liver disease, and side by side comparison of those miRNA markers with other markers of liver injury such as ALT should be gathered in future studies. [score:2]
Interactome analysis of miRNA-192 revealed activation of Smad signaling and ZEB proteins, which are related to alcoholic hepatitis pathobiology through regulation of TGFβ/Smad signaling [43]. [score:2]
We showed that miRNA-192 levels can be used to differentiate plasma from alcoholic hepatitis patients and plasma from controls. [score:1]
Curve of receiver operating characteristic (ROC) analysis constructed using differentially expressed d miRNA-122, e miRNA-192, and f miRNA-30a for discriminating alcohol-fed mice versus control mice. [score:1]
Importantly, of these miRNAs in the cohort of patients with alcoholic hepatitis, we found a significantly elevated level of miRNA-30a and miRNA-192 in the EV-fraction of plasma. [score:1]
Both miRNA-192 and miRNA-30a were significantly increased in the circulation of subjects with AH. [score:1]
Consistent with the highly significant increase of miRNA-122, miRNA-30a, and miRNA-192 (Fig.   4a–c), those miRNAs showed promising diagnostic values. [score:1]
Particularly, miRNA-122, miRNA-30a, and miRNA-192 showed the most substantial increases and revealed an excellent diagnostic value for differentiating alcohol-fed mice versus pair-fed mice. [score:1]
miRNA-192 showed consistently elevated levels in both alcohol-fed mice samples and in patient- derived alcoholic hepatitis samples. [score:1]
e, f Curve of receiver operating characteristic (ROC) analysis constructed for differentially expressed miRNA-30a, miRNA-192, and for discriminating patients with alcoholic hepatitis versus controls (*p < 0.05). [score:1]
Consistently, miRNA-30a and miRNA-192 were increased significantly in exosomes isolated from plasma of alcoholic hepatitis patients. [score:1]
Although we found significant discriminatory ability of exosomal miRNA-192 for alcoholic hepatitis, our study is in the discovery phase and has limited sample size. [score:1]
miRNA-192 showed promising value for the diagnosis of AH. [score:1]
The ROC analyses indicated excellent diagnostic value of miRNA-192, miRNA-122, and miRNA-30a to identify alcohol -induced liver injury. [score:1]
miRNA-192, miRNA-122 and miRNA-30a accurately discriminate the alcohol-fed and control mice. [score:1]
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In cultured human proximal tubular cells, we showed a similar TGF-β1 -driven downregulation of miR-192 expression, while forced expression of this transcript repressed ZEB1 and ZEB2 expression, thereby derepressing E-cadherin and exerting an anti-fibrotic effect [40]. [score:10]
In a rat remnant kidney mo del of renal fibrosis, low-dose treatment with anti-cancer agent paclitaxel improved renal function, inhibited Smad2/3 activation and downregulated miR-192 expression [55]. [score:8]
Further studies in diabetic apoE mice by Wang et al. identified a similar pattern of TGF-β1 -mediated downregulation of miR-192 leading to E-cadherin inhibition [41]. [score:6]
Conversely, upregulated miR-200b, miR-200c and miR-192 expression was observed in TGF-β -treated mouse mesangial cells [47]. [score:6]
Kato and colleagues observed that, in the early stages of renal injury, mouse mesangial cells treated with TGF-β1 showed upregulated expression of miR-192 and collagen alpha-2(I) [39]. [score:6]
For example, in streptozotocin -treated diabetic mice, miR-192 was downregulated by a locked nucleic acid -modified anti-miRNA in the renal cortex to improve renal fibrosis symptoms [52, 53]. [score:4]
Conversely, studies from this laboratory found decreased miR-192 expression in advanced-stage human DN renal biopsy samples accompanied by low estimated glomerular filtration rate and tubulointerstitial fibrosis [40]. [score:3]
We have since reviewed the pleiotropic roles of miR-192 in the kidney, with both anti- and pro-fibrotic effects that are apparently cell-type dependent [42]. [score:1]
Our recent work has provided definitive evidence of association of EVA urinary miR-16 and miR-192 with exosomes and NVA miR-16 and miR-192 with AGO2 [33]. [score:1]
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[+] score: 38
More specifically, following the initial analysis the ROC curves yielded the following AUCs: a) For MBs and control group; miR-192 (AUC = 0.841, up-regulated) (Figure  5C), b) For AT/RTs and control group; miR-34a (AUC = 0.9, up-regulated) (Figure  5J). [score:7]
On the contrary, though, Liu et al. [53] and Ferretti et al. [23] suggested that miR-192 was found significantly down-regulated in eight pediatric gliomas and in 34 pediatric MBs, respectively, whilst other reports in pediatric brain tumors have not identified this gene as differentially expressed [28, 29, 48, 49, 54]. [score:6]
Yet again, miR-192 was found up-regulated in the patient cohort, underlying the potential of this gene, which according to our findings it emerges not only as a putative diagnostic biomarker, but also as predictor for the likelihood of an inferior clinical outcome. [score:4]
Based on our findings, following both initial and meta-analyses, we report the up-regulation of miR-3681, miR-34a, miR-136, miR-26b and miR-192 in the patient group, subsequently leading to the conclusion that they might possess oncogenic activities. [score:4]
Based on the current findings, 8 miRNAs; miR-3681, miR-601, miR-320e, miR-34a, miR-642a, miR-136, miR-26b and miR-192 were found overexpressed in the patient group. [score:3]
Overexpression of miR-192 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma [50], and has been associated with early diagnosis of distant metastasis of gastric cancer [51], and with clinical relevance and prognostic significance in colon cancer [52]. [score:3]
Regarding brain tumors, our results are in line with Ruiz-Esparza-Garrido et al. [49], who manifested that miR-192 was up-regulated in 5 high-grade astrocytomas, when compared to 7 low-grade ones. [score:3]
Additionally, three miRNAs were found up-regulated in relapsed patients when compared to the group of patients that are in Complete Remission (CR) or the control group; mIR-192 (F), miR-320e (G) and miR-34a (H). [score:3]
Geng L, Chaudhuri A, Talmon G, Wisecarver JL, Are C, Brattain M, Wang J: MicroRNA-192 suppresses liver metastasis of colon cancer. [score:2]
MBs could be separated by miR-192 (C), miR-3617 (D) following initial analysis, whereas miR-3617 (E), miR-3912 (F), miR-4313 (G), miR-548j (H) and miR-548x (I) following meta-analysis. [score:1]
Given these, the role of miR-192 in childhood CNS malignancies remains to be elucidated. [score:1]
Moreover, we observed that miR-192 and miR-3617 could accurately discriminate MBs over the normal tissues indicating their potential as putative biomarkers for MB diagnostics. [score:1]
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[+] score: 37
To further understand whether decrease in microRNA signature expression predicts disease regression, scatter plots on miR-192 expression against histological scores were generated (Fig.   3b). [score:7]
Time -dependent expression of miR-122, miR-192, miR-21, miR-29a, miR-34a, and miR-505 in study 1. Data were expressed as minus delta Ct with reference to spike-in control miRNA. [score:5]
MicroRNA profiling in two independent cohorts of animals validated the up-regulation of 6 microRNAs (miR-122, miR-192, miR-21, miR-29a, miR-34a and miR-505) in NASH mice, which was designated as the circulating microRNA signature for NASH. [score:4]
Since miR-192 had the highest association with other microRNAs and disease pathologies (NAS, r = 0.78), it was chosen to build the new composite biomarker. [score:3]
b Scatter plots of miR-192 expression (reference to spike-in control) against histopathological scores: inflammation, macrovesicular vacuolation, perisinusoidal fibrosis and portal fibrosis Clinical diagnosis of NASH requires the histological examination of liver biopsies [23]. [score:3]
Similarly, we observed slightly decrease in the liver miR-122 and miR-192 expression (not statistically significant) in NASH mice compared to lean mice. [score:2]
The right panel depicted the expression level of miR-192 and miR-505 in mice having NAS > 3 compared with mice having NAS ≤ 3. c ROC curves of the microRNA signature in predicting mice having NAS > 3 (AUC = 0.897, 95% confidence interval: 0.75 - 1) in study 1. The confusion matrix was depicted in the inset (numbers in rows are actual classification, numbers in columns are predicted classification). [score:2]
To further improve the performance of microRNA -based biomarker, a new composite biomarker was proposed, which consists of miR-192, miR-21, miR-505 and ALT. [score:1]
MiR-192 and miR-122 fell into the same category, and both were implicated in liver injury and hepatocyte death [28, 29]. [score:1]
In view of the biological function of each feature, the new composite biomarker could potentially reflect the status of the liver from the following perspectives: miR-192 and ALT serve as independent indicator of hepatocyte function, miR-21 suggests of stellate cell activation and liver fibrosis, miR-505 implies for pathological manifestations. [score:1]
a, b Univariate ROC analysis of miR-192 and miR-505, which was created by plotting the true positive rate (sensitivity) against false positive rate (1-specificity). [score:1]
b, c ROC curves of the miR-192, miR-21, miR-505 and ALT in predicting mice having NAS > 3 in study 1 (AUC = 0.948, 95% confidence interval: 0.827 - 1) and study 3 (AUC = 0.931, 95% confidence interval: 0.845 - 1). [score:1]
Univariate ROC curve analysis showed that miR-192 and miR-505 achieved the greatest AUROC of 0.923 and 0.919 respectively in discriminating mice had NAS > 3, while miR-122, miR-29a, miR-34a and miR-21 had an AUROC of 0.88, 0.84, 0.80 and 0.79 (Fig.   4a and b). [score:1]
Based on these findings, a microRNA -based composite biomarker consisting of miR-192, miR-21, miR-505 and ALT was proposed, which demonstrated great performance in distinguishing between lean and NASH mice (NAS > 3). [score:1]
We then tested the performance of the new composite biomarker consisting of miR-192, miR-505, miR-21 and ALT in discriminating NASH animals (NAS > 3) from healthy mice (NAS ≤ 3) in study 1 and 3. As shown in Fig.   5b, the new biomarker outperformed the microRNA signature plus ALT mo del, and achieved AUROC of 0.958 with further reduction of one misclassified animal in study one. [score:1]
c Principle component analysis (PCA) of miR-192, miR-122, miR-21, miR-29a, miR-34a, and miR-505 in study 2. Red dots represented NASH mice (mice on 3H diet for 7 months), and green dots represented lean mice. [score:1]
The top six common microRNAs including miR-21, miR-122, miR-192, miR-29a, miR-34a and miR-505, were designated as the circulating microRNA signature for NASH (Fig.   2b). [score:1]
It was clear that diet-switching group animals had lower level of circulating miR-192 accompanied with improved liver histological lesions. [score:1]
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Furthermore, Georges et al. [78] define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G1 and G2 checkpoints. [score:6]
Braun et al. [79] found that the expression of miRNA-192/215 was down-regulated in cancer tissue compared to normal mucosa. [score:5]
The same miRNAs were also up-regulated by DNA damage in a p53 -dependent fashion like miR-34a [78], and in accordance with our results, activation of miR-192/215 induces cell cycle arrest, suggesting that these miRNAs operate in the p53 network. [score:4]
This evidence highlights the important role of miR-192 in CRC development and supports the idea that miR-192 might carry out a tumor suppression function. [score:4]
Of these transcripts, 18 transcripts are direct targets of miR-192/215; finally, the authors concluded that observed cell cycle arrest most likely results from a cooperative effect among the modulations of these genes by the miRNAs. [score:4]
According with recent studies [78, 79], we found an anti-proliferative effect of miR-192/215 overexpression in CRC cell lines. [score:3]
Moreover, two studies found a downregulation of miR-192 in CRC tissues when compared to the normal colon [80, 81]. [score:3]
Braun et al. [79], using a direct pharmacologic activator of p53 identified two clusters of miRNAs comprising miR-192/215 regulated by p53. [score:3]
Moreover, we found that miR-192/215 increases p21 expression. [score:3]
On the other hand, we showed recently the functional effects of miR-192/215 on cell cycle, likely due to their pleiotropic mechanism of action, reduce the 5-fluorouracil (5-FU) activity. [score:1]
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A correlation analysis on gene expression confirmed the regulation of miR-192 by HNF1A (Pearson's rho of 0.59) as reported by Khella et al. [23] however proposed targets, such as FZD6, show a weak correlation in the TCGA data (Pearson's rho of −0.31). [score:6]
The miR-192/194 cluster has been reported to depend on the p53 mutation status in multiple myeloma, hepatocellular, and renal diseases but this association has not been studied in RCC [32, 33]. [score:4]
Here, we observe that the two patient groups characterized by low miR-192 expression levels (group 1 and group 5) also display a higher p53 mutation rate than the other groups (Fisher exact test p-value: 0.0022) hence linking the regulation of miR-192 by p53 to ccRCC. [score:3]
Despite their similarities, group 5 differs from group 6 by a higher number of stage IV patients (38% vs 22%), a worse survival, and low miR-192 expression levels. [score:3]
miR-192 expression levels highly correlate with their subtype classification (Wilcoxon test p-value: 1.95×10-11) and could also act as a subtype predictor (area under ROC curve of 0.7). [score:3]
Of note, there seems to be two groups of normal samples (group “N” and part of group 1) that differ in in their miR-192 and miR-183 expression levels. [score:3]
Interestingly, miR-192 expression does not significantly correlate with tumor stage (Wilcoxon test between early and late stage patients) and hence might be a marker for two different ccRCC subtypes. [score:3]
Both proteins have relations with the actin cytoskeleton [25, 26], which strengthens the hypothesis that miR-192 is involved in the epithelial-mesenchymal transition and metastases [23, 27]. [score:1]
A clustering procedure revealed the presence of 5 distinct miRNA clusters, which were best represented by miR-21, miR-146b-3p/5p, and miR-155 for cluster 1, miR-1 and miR-143 for cluster 2, miR-10b for cluster 3, mir-194-3p and miR-192-3p/5p for cluster 4, and miR-182, miR-183, and miR-221 for cluster 5 (Fig. 1). [score:1]
In that respect, miR-192 is of primary interest as it has been well studied but never reported as a potential biomarker for ccRCC. [score:1]
That is miR-21, miR-10b, miR-143, miR-183, and miR-192, which will be further referred to as the “top miRs” signature. [score:1]
miR-21, miR-10b, miR-143, miR-183, and miR-192 define a prognosis signature in ccRCC. [score:1]
However, there was no correlation in miR-192 levels between normal and tumor tissue in matched samples. [score:1]
Our in silico analysis unveiled a novel ccRCC-specific 5-miRNA (miR-10b, miR-21, miR-143, miR-183, and miR-192) signature able, when combined with information from conventional TNM staging and the age of the patient, to prognosticate ccRCC outcome more accurately than known ccRCC miRNA signatures or TNM staging alone. [score:1]
All of them have been reported to play a role in cell proliferation or metastasis but miR-192 and miR-183 have never been included in a miRNA signature for ccRCC. [score:1]
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[+] score: 31
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-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-181c, 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
Izzotti et al. (2009a, b) have monitored the expression of 484 miRNAs in the lungs of mice exposed to cigarette smoking, the most remarkably downregulated miRNAs belonged to several miRNA families, such as let-7, miR-10, miR-26, miR-30, miR-34, miR-99, miR-122, miR-123, miR-124, miR-125, miR-140, miR-145, miR-146, miR-191, miR-192, miR-219, miR-222, and miR-223. [score:6]
The expression of ERCC3 and ERCC4 were reduced when miR-192 was overexpressed. [score:5]
MiR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells. [score:4]
A recent study showed that miR-192 directly targets a NER -associated protein (Georges et al., 2008). [score:4]
A bioinformatic analysis of miRNAs which potentially played a role in NER, show that miR-192, was the most differentially upregulated miRNA. [score:4]
Enhanced MMP2 and MMP9Gramantieri et al., 2007; Meng et al., 2007; Li et al., 2008; Garofalo et al., 2009; Ji et al., 2009a; Pogribny et al., 2009; Wang et al., 2010; Song et al., 2013 miR-182 MetastasisWang et al., 2008, 2012b; Wong et al., 2008, 2010 miR-183 Onset and progression, ApoptosisWang et al., 2008; Wong et al., 2008, 2010; Liang et al., 2013 miR-185 MetastasisBudhu et al., 2008; Wong et al., 2008, 2010; Huang et al., 2009; Zhi et al., 2013 miR-192 Inhibition of DNA excision repairXie et al., 2011 miR-194 MetastasisBudhu et al., 2008; Huang et al., 2009; Meng et al., 2010; Xu et al., 2013 miR-195 Proliferation, colony formation. [score:3]
Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. [score:2]
Wang et al. (2009a) found increase serum concentration of hepatocyte-specific miRNAs including miR-122 and miR-192 within 1 h after acetaminophen exposure. [score:1]
Potential microRNAs that could serve as possible markers of HCC by exposure to aflatoxins are miR-27a, miR-27b, miR-122, miR-148, miR-155, miR-192, miR-214, miR-221, miR-429, and miR-500. [score:1]
Since of AFB1 is an important risk factor of HCC and AFB1-DNA adducts are known to be repaired by NER, dietary AFB1 exposure could impaired NER mediated by miRNAs like miR-192. [score:1]
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[+] score: 30
In order to further understand the role of aberrant miRNAs in physiological functions and biologic processes in arsenite -induced neoplastic transformation cells, 11 downregulated miRNAs (miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, and miR-33b-5p) and six upregulated miRNAs (miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, and miR-141-3p) (Table S2) were selected, and their target genes were predicted with the TargetMiner, miRDB, and TarBase databases. [score:11]
Among the 191 dysregulated miRNAs, seventeen miRNAs (downregulation miRNAs: miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, miR-33b-5p; upregulation miRNAs: miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, miR-141-3p, Table S2) were selected for bioinformatics analysis. [score:8]
Jin H. Qiao F. Wang Y. Xu Y. Shang Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathwayOncol. [score:8]
Furthermore, the miRNA profile of the arsenite -induced neoplastic transformation in our study showed that a series of miRNAs is often dysregulated in lung cancer, e. g., let-7 family, miR-200 family, miR-125a, miR-145, miR-192, miR-145, miR-335 [36]. [score:2]
We determined the level of six miRNAs (miR-33b-5p, miR-15b-5p, miR-192-5p, miR-141-3p, miR-200b-3p, and miR-106b-5p) to validate the reliability of the miRNA Array detection. [score:1]
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miR-192 is upregulated by genotoxic stress in HCT116, A549 and U2OS cell lines bearing wild-type p53, and induces the cell cycle arrest by enhancing CDKN1A/p21 expression (18, 30). [score:6]
Our miRNA hits also included tumor suppressive miR-7, miR-124a, miR-192 and miR-193a in several cancer types (18, 25– 27), suggesting that these miRNAs could be tumor suppressive in ovarian cancer. [score:5]
We examined whether miR-124a, miR-192, miR-193a and miR-193b affected DNA synthesis to inhibit cell proliferation in A2780 cells. [score:3]
Inhibitory effects of miR-124a and miR-192 on cell cycle gene pathway are reported in several cancer cell lines. [score:3]
They included known oncogenic miRNAs such as miR-372 (cell viability, 187%) and miR-373 (165%), and tumor suppressive miRNAs such as miR-124a (28.3%), miR-7 (37.1%), miR-192 (36.6%) and miR-193a (29.7%) in several different cancer types (18, 25– 27). [score:3]
miR-124a and miR-192 induced a decrease in BrdU incorporation, indicating that these miRNAs affected cell cycle resulting in inhibition of DNA synthesis in A2780 cells. [score:3]
As shown in Fig. 2A, miR-124a, miR-192, miR-193a and miR-193b decreased an incorporation of BrdU compared with the negative control, indicating that these miRNAs induced the inhibition of DNA synthesis in A2780 cells. [score:2]
We discovered pro-proliferative miRNAs (miR-9 [*], miR-93, miR-130a, miR-130b, miR-301, miR-302b, miR-302d, miR-363, miR-372, miR-373), and anti-proliferative miRNAs (miR-7, miR-124a, miR-192, miR-193a, miR-193b, miR-199a [*], miR-432 [*], miR-497, miR-506, miR-517c) in A2780 cells. [score:1]
We found several anti-proliferative miRNAs including miR-124, miR-192 and miR-193 in A2780, suggesting that the potential of miRNA screens for discovering miRNAs as therapeutic tools to treat ovarian cancer. [score:1]
We confirmed results of our first screening at 50 nM, and found that the transfection of miR-124a, miR-192, miR-193a and miR-193b induced a large decrease in the cell viability of A2780 even at 5 nM (Fig. 1B), indicating that these miRNAs had a profound anti-proliferative effect in A2780 cells. [score:1]
We found that miR-193a and miR-193b but not miR-124a and miR-192 induced more than twofold increase in an activity of caspase 3/7, the effector of apoptotic pathway, in A2780 cells (Fig. 2B). [score:1]
To further evaluate miRNA mimics on the inhibition of cell proliferation in A2780, we selected top 10 anti-proliferative miRNAs (miR-7, miR-124a, miR-192, miR-193a, miR-193b, miR-199a [*], miR-432 [*], miR-497, miR-506 and miR-517c) from the first screen, and examined the cell viability in A2780 cells transfected with different concentrations of miRNAs (5, 25, 50 nM). [score:1]
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[+] score: 30
These studies revealed that the X-linked inhibitor of apoptosis (XIAP) was a novel transcription target of miR-192-5p and miR-215 in non-small cell lung cancer [165]. [score:5]
Expression of WT TP53 in TP53-mutant H1299 resulted in miR-192-5p and miR-215 expression after CUR treatment. [score:5]
Increased miR-192-5b expression in A549 cells resulted in decreased proliferation and increased apoptosis while suppression of miR-192-5b had the opposite effects. [score:5]
The effects of CUR were shown to be dependent on miR-192-5p and miR-215 expression. [score:3]
miR-192-5p and miR-215 functioned as tumor suppressors in these cells. [score:3]
CUR increased miR-192-5p expression while it decreased PI3K/PTEN/Akt activity. [score:3]
This was shown to be mediated by CUR inducing miR-192-5b expression in A549 cells. [score:3]
miR-192-5p mimic could increase the effects of CUR [166]. [score:1]
CUR activated both miR-192-5p and miR-215 in TP53 WT A427 cells. [score:1]
CUR has been shown to activate the TP53/miR-192-5p/miR-215/XIAP pathway in NSCLC. [score:1]
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[+] score: 29
Note that miR -3065, -944 and -149-5p all were down-regulated and share multiple common targets (Panel A) and miR-192 and -215 all were up-regulated and share common targets (Panel B). [score:11]
0054240.g003 Figure 3 Note that miR -3065, -944 and -149-5p all were down-regulated and share multiple common targets (Panel A) and miR-192 and -215 all were up-regulated and share common targets (Panel B). [score:11]
We examined the expression of the ten most over- (miR-192-5p, 103a-5p, 145-5p, -215, -451a, -23b-3p, -21-5p, 23a-3p, 24-3p, 191-5p) and under- expressed (miR-491-3p, -574, -18a, -488-5p, -216a, -548, -520d, -20b, -218, -346) human BE miRNA in three BE cell lines, BAR-T, CP-A and CP-C. The mean number of reads by NGS for the ten most expressed miRNA in human BE specimens was 78178 (range 27,374–240,611). [score:7]
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[+] score: 27
Other miRNAs from this paper: hsa-mir-21, hsa-mir-215, hsa-mir-221, hsa-mir-222
In addition, the identification of the long 3′ UTR of human IL-21 mRNA and transfection studies revealed that human IL-21 mRNA with the long 3′ UTR is down-regulated by miR-21, miR-192, miR-215, miR-221, and miR-222, which were in the top 25 miRNAs up-regulated by. [score:7]
Collectively, the present study is the first demonstration that human IL-21 mRNA is down-regulated by miR-21, miR-192, miR-215, miR-221, and miR-222, suggesting a novel regulatory mechanism of IL-21 expression in immune responses. [score:7]
While the expression of miR-192 in patients infected with HBV was not reported, its expression in HepG2.2.15 cells was higher than parental HepG2 cells [38]. [score:5]
s revealed that miR-21, miR-192, miR-215, miR-221, and miR-222 repressed the expression of the reporter gene with the long 3′ UTR of human IL-21 mRNA (Fig.   3A). [score:3]
In this study, we have shown that the expression of human IL-21 in T cells was repressed by transduction of miR-21, miR-192, miR-215, miR-221, and miR-222. [score:3]
Interestingly, it was reported that miR-21, miR-192, miR-215, miR-221, and miR-222 were enriched in exsosomes derived from sera of cancer patients and supernatants of cancer cells 42– 47. [score:1]
In the long 3′UTR of human IL-21 cDNA we identified, there are multiple conserved miRNA binding sites for miR-21, miR-192, miR-215, miR-221, and miR-222, (Fig.   2D and Fig.   S4). [score:1]
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[+] score: 25
0037395.g003 Figure 3(A) Serum miR-122 expression levels; (B) Serum miR-192 expression levels; (C) Serum miR-193 expression levels; (D) Biochemical parameter: serum ALT levels; (E) Biochemical parameter: serum AST levels. [score:7]
0037395.g004 Figure 4(A) Serum miR-122 expression levels; (B) Serum miR-192 expression levels; (C) Serum miR-193 expression levels; (D) Biochemical parameter: serum ALT levels; (E) Biochemical parameter: serum AST levels; The absolute concentrations of target miRNAs were calculated by referring to calibration curves developed with corresponding synthetic miRNA oligonucleotides. [score:7]
By individual TaqMan qRT-PCR analysis of dysregulated serum miRNAs uncovered by serum TLDA and dysregulated liver tissue miRNAs uncovered by microarray hybridization in primary screening, 6 serum miRNAs, including miR-122, miR-192, miR-193, miR-200a, miR-21 and miR-29c, exhibited a high correlation with primary screening results. [score:3]
Among this set of serum miRNAs, miR-122, miR-192 and miR-193 presented a significant change in both DILI mo del groups within the threshold of a fold change >10 and P-value<0.05 (Table 1). [score:1]
In the dose -dependent analysis of the serum miRNAs miR-122, miR-192 and miR-193, miR-122 showed extremely high sensitivity in both 2 DILI mo del groups (fold change >50.0), while serum biochemical parameters (e. g., ALT and AST) displayed only mild sensitivity (fold change <20.0) in the high-dose group. [score:1]
In the time -dependent analysis of the serum miRNAs miR-122, miR-192 and miR-193, all of these serum miRNAs exhibited an ascending trend 3 h after administration in both DILI mo del groups (fold change >2.0); while serum biochemical parameters (e. g., ALT and AST) remained at baseline levels (fold change <1.5). [score:1]
Beside, among the three serum miRNAs as potential diagnostic biomarker for DILI explored in rat mo dels in present study, miR-122 and miR-192 was also validated in plasma of mice mo dels by Wang et al. [27]. [score:1]
Previously, plasma miR-122 and miR-192 had been reported increased linearly from 1 to 3 hours and displayed dose -dependent manner after APAP overdosing in mice. [score:1]
The panel of aberrantly expressed serum miRNAs (miR-122, miR-192 and miR-193) all exhibited time- and dose -dependent characteristics. [score:1]
In summary, serum miR-122, miR-192 and miR-193 constitute a new panel for compound- and herb -induced liver injury diagnosis. [score:1]
Our results demonstrate that a new panel of serum miRNAs (miR-122, miR-192 and miR-193) could have the potential to serve as sensitive, specific and noninvasive biomarkers for the diagnosis of DILI. [score:1]
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Reduced expression of miR-192, miR-215 and miR-10b in liver samples of rat from fish oil group (Fig. 3B) resulted in a de-repression of their targets plasminogen activator inhibitor type 1 (Serpine1) and insulin-like grow factor 2 (Igf2), as both genes have predicted binding sites for these three miRNAs. [score:7]
Among the validated gene targets of some of these miRNAs, there is the insulin grown factor pathway (Igf-1r and Igf-1), which is targeted by miR-192 and miR-215 [33]. [score:5]
By contrast, miR-26b-5p, miR-199a-3p, miR-377–3p, miR-let-7f-5p, miR-200a-3p, miR-21–5p, miR-152–3p, and miR-192–5p expressions were repressed by SO diet consumption. [score:3]
Moreover, Igf2 and Serpine1 are among predicted targets of this family of miR-192/215. [score:3]
Igf2 and Serpine1 are targets of miR-192/215 and miR-10b family. [score:3]
Adult offspring of rats that were fed the FO diet during the first 12 days of pregnancy showed lower expression of miR-192 compared with SO, OO, LO, and PO diets. [score:2]
Likewise, we observed a decrease in the expression of several hepatic miRNAs, namely miR-192–5p, miR-10b-5p, miR-377–3p, and miR-215 after FO compared with OO and PO diets and miR-21–5p and mir-26b-5p after FO compared with PO diets. [score:1]
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Nuclear run on assay showed that excessive CUDR enhanced and CUDR knockdown inhibited the expression of miR21, miR155, miR17, miR675, miR372, miR192 (Figure S5B). [score:5]
3) CUDR overexpression enhanced the expression of miR21, miR155, miR17, miR675, miR372, miR192; 4) CUDR enhanced the loading of pStat3 on the promoter region of CUDR, HOTAIR, MALAT1, HULC, H19. [score:5]
As shown in Figs 6a and S5A, excessive CUDR enhanced and CUDR knockdown inhibited the loading of pStat3 on the promoter region of miR21, miR155, miR17, miR675, miR372, miR192. [score:4]
2) CUDR overexpression increased the miR21, miR155, miR17, miR675, miR372, miR192 promoter luciferase activity. [score:3]
To elucidate whether CUDR alters the expression of microRNAs and lncRNAs through pStat3 under the inflammatory condition, we first performed with anti-pStat3 followed by PCR with miR21, miR155, miR17, miR675, miR372, miR192 promoter primers in IL6 treated hepatocyte-like cells transfected with pCMV6-A-GFP, pCMV6-A-GFP-CUDR, pGFP-V-RS, pGFP-V-RS-CUDR. [score:2]
Excessive CUDR increased and CUDR knockdown decreased the miR21, miR155, miR17, miR675, miR372, miR192 promoter luciferase activity (Fig. 6b). [score:2]
The conclusion is supported by results from nine parallel sets of experiments: 1) CUDR enhanced the loading of pStat3 on the promoter region of miR21, miR155, miR17, miR675, miR372, miR192. [score:1]
Importantly, the phosphorylated Stat3 loads onto the promoter region of miR21, miR155, miR17, miR675, miR372, miR192, CUDR, HOTAIR, MALAT1, HULC, H19, as well as excessive CUDR and IL6 increases DNA methylation of MEG3, TERRA promoter region. [score:1]
That phosphorylated Stat3 loads onto the promoter region of miR21, miR155, miR17, miR675, miR372, miR192, CUDR, HOTAIR, MALAT1, HULC, H19 enhances these noncoding RNAs outcome. [score:1]
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Finally, given that PTEN has been shown to be a hypothetical gene target for miR106b and miR-494, BAX for miR-128, and BIM (or BCL2L11) for miR-192, their gene expression was analyzed by means of quantitative Real-time PCR analysis (Supplementary Figure 5). [score:5]
Figure 5 Since miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494 were found downregulated and have been shown to induce chemoresistance (Figure 5), we evaluated the expression of some of them, including miR-15b (Hs04231486_s1), miR-23a (Hs03659093_s1) and miR-29a (Hs03849009_s1), through TaqMan microRNA expression assays (Supplementary Figure 4). [score:5]
Figure 5Since miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494 were found downregulated and have been shown to induce chemoresistance (Figure 5), we evaluated the expression of some of them, including miR-15b (Hs04231486_s1), miR-23a (Hs03659093_s1) and miR-29a (Hs03849009_s1), through TaqMan microRNA expression assays (Supplementary Figure 4). [score:5]
We found that some miRNAs, including miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494, were downregulated in MDA-MB-231 cells under STS conditions. [score:4]
MiR-15b and miR-23a have been shown to increase Cisplatin-resistance in lung cancer cell line A549 [28] and in tongue squamous cell carcinoma [29], whereas miR-29a induced Adriamycin and Docetaxel resistance in breast cancer (BC) [30], miR-128 enhanced antiblastic resistance in BC cells targeting BAX [31], miR-192 promoted Cisplatin-resistance in lung cancer cells A549/DDP [32], and, finally, miR-106b and miR-494 conferred radioresistance and Sorafenib-resistance in colorectal cancer and hepatocellular carcinoma silencing PTEN and p21 [33– 35]. [score:3]
Among miRNAs involved in chemotherapy response, miR-26a, miR-106b, miR-128 and miR-192 were not found significantly deregulated. [score:2]
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[+] score: 22
Interestingly, 7 of the 12 miRNAs that were up-regulated in the presence of IFN-α (miR-30b,miR-30c, miR-130a, miR-192, miR-301, miR-324-5p and miR-565) were also down-regulated in HCV -infected Huh7.5 cells. [score:7]
Seven miRNAs (miR-30b, miR-30c, miR-130a, miR-192, miR-301, miR-324-5p, and miR-565) were down-regulated in HCV-infected Huh7.5 cells (p<0.05) and subsequently up-regulated following interferon-α treatment (p<0.01). [score:7]
The GOMir tool JTarget, using five major miRNA-mRNA prediction databases, identified a list of mRNA targets for miR-30, miR-130a, miR-192, miR-301 and miR-324-5p [21]. [score:5]
Anti-miRs specific for 5 miRNAs down regulated upon HCV infection (miR-30b, miR-30c, miR-130a, miR-192, and miR-324-5p) were tested against a mock -transfected HCV [+] Huh7.5 cell control (Fig. 2). [score:2]
No effect on HCV replication was observed with miR-30b, miR-192 and miR-324-5p in vitro. [score:1]
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When the same mo del was analyzed by Zhou et al. [19], peritoneal fibrotic tissues displayed upregulation in 8 miRNAs (miR-205, miR-664, miR-352, miR-146b-5p, predicted miR-160, miR-132, miR-15b, and let-7d) while 15 were downregulated (miR-335, miR-923, miR-801, miR-200a, miR-801, miR-30a, miR-193a-3p, miR-193b, miR-29b, miR-203, miR-148a, miR-709, miR-192, miR-15a, and miR-26b) [19]. [score:7]
Total PDE-derived cells from 110 PD patients (82 new, 28 prevalent) showed significant miRNA upregulation of miR-15a, miR-21, and miR-192 when comparing new, prevalent and UF groups, while miR-17, miR-30, and miR-377 expression was similar between groups [36]. [score:6]
Lin et al. found robust and significant downregulation of 8 miRNAs in the hypertonic dialysate group (miR-31, miR-93, miR-100, miR-152, miR-497, miR-192, miR-194, and miR-200b) and increased expression of miR-122 was observed in the hypertonic dialysate group compared with the saline and control groups [26]. [score:5]
Chen et al. [36] selected the following candidate miRNAs based on a report on EMT and kidney disease [46]: miR-15a, miR-17-92, miR-21, miR-30, miR-192, miR-216a, miR-217, and miR-377 [36]. [score:3]
Among them, only miR-192 overlapped with the miRNAs described by Lin et al. [19, 26]. [score:1]
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Dysregulation of 7 of these miRNAs coincides with our results (upregulation of hsa-let-7i-5p, hsa-miR-21-5p and hsa-miR-146a-5p; downregulation of hsa-miR-192-5p, hsa-miR-194-5p and hsa-miR-200b-3p). [score:8]
We could confirm the upregulation of hsa-miR-21-5p and the downregulation of hsa-miR-192-5p. [score:7]
controls (FC = 5.06), most likely due to the downregulation of hsa-miR-192-5p (FC = -2.98). [score:4]
Wu et al. [13] identified the chemokine macrophage inflammatory protein 2-α (MIP-2α or CXCL2) as target mRNA of hsa-miR-192-5p. [score:3]
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Furthermore, the decreased expression of miR-192 seems to correlate directly with tubulointerstitial fibrosis and a low glomerular filtration rate, and TGF-β suppresses miR-192 expression in cultured proximal tubular cells [26]. [score:8]
On the other hand, miR-192 and miR-194 were highly expressed in the kidney and small intestine, and miR-449a was highly expressed in the lung (Figures 3(d) and 3(e)). [score:5]
miR-192 and miR-194 were highly expressed in the kidney and in the small intestine. [score:3]
The expression of miR-200a, miR-200b, miR-200c, miR-192, miR-194, and miR-449a was validated with real-time RT-PCR in rat tissues in order to discriminate the kidney from other tissues with a tubular structure. [score:3]
Consistently, the plasma concentrations of the miR-200 family members and miR-192 and miR-194 increased significantly. [score:1]
A significant increase in plasma miR-200a/b/c, miR-192, and miR-194 levels was observed in the AKI mo del. [score:1]
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The sequencing results for seven highly expressed miRNAs (hsa-mir-145, hsa-mir-29a, hsa-mir-29c, hsa-mir-21, hsa-mir-451a, hsa-mir-192 and hsa-mir-148a) were validated using singleplex real-time PCR (qRT-PCR) to determine their expression levels in the gastric antrum region of 10 healthy individuals. [score:5]
Of the seven miRNAs that were simultaneously expressed in both tissues, five miRNAs maintained a relatively similar expression level after normalization: hsa-mir-29c, hsa-mir-21, hsa-mir-451a, hsa-mir-192 and hsa-mir-148a (Table 2). [score:5]
The high miRNA expression levels demonstrated by ultra-deep sequencing (in descending order of expression level : hsa-mir-145, hsa-mir-29a, hsa-mir-29c, hsa-mir-21, hsa-mir-451a, hsa-mir-192 and hsa-mir-148a) were validated using TaqMan miRNA assays (Life Technologies). [score:4]
Hsa-mir-192 is upregulated in gastrointestinal organs and kidney [9]. [score:4]
After filtering and aligning using with MirBase, 148 mature miRNAs were identified in the gastric antrum tissue, totaling 3,181 quality reads; 63.5% (2,021) of the reads were concentrated in the eight most highly expressed miRNAs (hsa-mir-145, hsa-mir-29a, hsa-mir-29c, hsa-mir-21, hsa-mir-451a, hsa-mir-192, hsa-mir-191 and hsa-mir-148a). [score:3]
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[+] score: 20
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-16-1, hsa-mir-21, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-9-2, mmu-mir-151, mmu-mir-10b, mmu-mir-194-1, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-122, hsa-mir-10a, hsa-mir-10b, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-210, hsa-mir-214, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-194-1, mmu-mir-192, 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-16-1, mmu-mir-16-2, mmu-mir-21a, mmu-mir-10a, mmu-mir-210, mmu-mir-214, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-9-1, mmu-mir-9-3, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-365a, mmu-mir-365-1, hsa-mir-365b, hsa-mir-151a, gga-let-7i, gga-let-7a-3, gga-let-7b, gga-let-7c, gga-mir-16-1, gga-mir-194, gga-mir-10b, gga-mir-199-2, gga-mir-16-2, gga-let-7g, gga-let-7d, gga-let-7f, gga-let-7a-1, gga-mir-199-1, gga-let-7a-2, gga-let-7j, gga-let-7k, gga-mir-122-1, gga-mir-122-2, gga-mir-9-2, mmu-mir-365-2, gga-mir-9-1, gga-mir-365-1, gga-mir-365-2, hsa-mir-151b, mmu-mir-744, gga-mir-21, hsa-mir-744, gga-mir-199b, gga-mir-122b, gga-mir-10a, gga-mir-16c, gga-mir-214, sma-let-7, sma-mir-71a, sma-bantam, sma-mir-10, sma-mir-2a, sma-mir-3479, sma-mir-71b, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-let-7k, gga-mir-365b, sma-mir-8437, sma-mir-2162, gga-mir-9-3, gga-mir-210a, gga-mir-9-4, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3, gga-mir-9b-1, gga-mir-10c, gga-mir-210b, gga-let-7l-1, gga-let-7l-2, gga-mir-122b-1, gga-mir-9b-2, gga-mir-122b-2
As shown in Fig. 2, the levels of miR-192, miR-194 and miR-122 in serum do not change between 4–12 weeks post infection, whereas five of the miRNAs that are up-regulated in the liver are also significantly elevated in serum at 12 weeks post infection (p<0.05), ranging from 2.6 fold (miR-21) to 4.7 fold (miR-214) (Table S2). [score:4]
Temporal expression analysis of miR-199, miR-214, miR-21, miR-210, miR-122, miR-192 and miR-194 in the liver during S. mansoni infectionBetween weeks 6 and 12, female parasites continue to produce ∼300 eggs per day [51], resulting in an increase in the number of granulomas in the liver and the development of fibrosis [45]. [score:4]
However, according to our analysis, although miR-192, miR-122 and miR-194 were down-regulated in the liver during infection, their levels in serum did not change significantly (Fig. 1– 2). [score:4]
A number of reports have demonstrated an increase in miR-122 and miR-192 in plasma or serum upon viral infection as well as chemically induced liver disease [54], [56]. [score:3]
Temporal expression analysis of miR-199, miR-214, miR-21, miR-210, miR-122, miR-192 and miR-194 in the liver during S. mansoni infection. [score:3]
Consistent with the array results, there was an increase in miR-199-5p, miR-199-3p, miR-214, miR-21, miR-210, and a reduction of miR-192, miR-194, miR-365, miR-122 and miR-151 in the liver tissue of S. mansoni infected mice as compared to naïve mice; miR-9 and miR-744 did not display differential expression and were not analysed further (Table 1). [score:2]
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[+] score: 18
Mature miRNA expression could be classified into two groups: i) cardia-tissues: miRNAs rarely expressed in other tissues but expressed in gastric cardia, including miR-148a, miR-192, miR-200a and miR-200b; ii) quasi-ubiquitous: miRNAs expressed in many tissues and conditions, including miR-29c, miR-21, miR-24, miR-29b, miR-29a, miR-451, miR-31, miR-145, miR-26a, miR-19b and let-7b. [score:9]
The expression of mir-148a and mir-192 had been identified in other normal and cancerous human tissues, but was not over-expressed. [score:5]
The high expression levels of miRNAs identified by ultra-deep sequencing (in descending order: miR-29c, miR-21, miR-148a, miR-29a, miR-24, miR-29b, miR-192, miR-451, miR-145, miR-31, miR-200a, miR-19b, miR-200b, let-7b and miR-26a) were validated with the TaqMan miRNA assays (Life Technologies). [score:2]
hsa-miR-192 NFAT5 ; DDX6 ; IGF1 ; DICER1 ; CREB5 ; C6orf168; CTNNBIP1; ZBTB34; COL5A1; PPP1R3D; NCOA3; XPO4; SLC5A3; SH3RF3; CDON; DIAPH2; DBT; FAM167A; CCNT2; IKZF2. [score:1]
The SOLiD platform showed that miR-192 and 148a are specific to gastric tissue. [score:1]
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[+] score: 17
Chau and colleagues [28] showed that genotoxic stress could lead to up-regulation of miR-192 and miR-215, which in turn lead to a gene expression signature that is highly enriched for regulators of cell cycle. [score:7]
Therefore, factors other than p53 are responsible for the increase in miR-192 and miR-215 expression level. [score:3]
These results imply that miR-192 and miR-215 work in synergy with the p53 pathway in regulating cell cycle arrest and thus they are critical to tumor formation. [score:2]
Furthermore, miRNAs is implicated in every aspect of cellular outcome of p53 activation: apoptosis (miR-34 and miR-29), cell cycle arrest (miR-192, miR-194, and miR-215), and senescence (miR-34). [score:1]
The miR-34 story set the precedence and a number of papers have now been published showing that other miRNAs interfere the p53 pathway, in a p53-independent manner (miR-34), partial p53 -dependent manner (miR-192, miR-194, miR-215, and miR-21) or a p53 -dependent manner (miR-29). [score:1]
miR-192 and miR-215 Induces p53-Mediated Cell Cycle Arrest. [score:1]
Thus, miR-192, miR-194 and miR-215 are regarded as an amplifier to p53 and p53 -dependent mediators of cell cycle arrest. [score:1]
In a recent paper published by Dobbelstein and colleagues [26] p53 was shown to induce, together with miR-34a, three additional miRNAs: miR-192, miR-194, and miR-215. [score:1]
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[+] score: 16
2015.2749 26640527 6. Jin H. Qiao F. Wang Y. Xu Y. Shang Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of mir-192-5p and suppression of PI3K/Akt signaling pathwayOncol. [score:8]
It has been published that curcumin inhibited the proliferation and induced the apoptosis of non-small-cell lung carcinoma cells (A549 cell line) by the up-regulation of microRNA-192-5p and suppression of the PI3K3/Akt signaling pathway [6]. [score:8]
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[+] score: 16
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-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-30a, hsa-mir-31, hsa-mir-98, hsa-mir-99a, hsa-mir-101-1, hsa-mir-16-2, hsa-mir-197, hsa-mir-199a-1, hsa-mir-208a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-187, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-211, 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-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-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-140, hsa-mir-142, hsa-mir-143, hsa-mir-144, 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-126, hsa-mir-138-1, hsa-mir-146a, hsa-mir-200c, hsa-mir-155, hsa-mir-128-2, 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-30e, hsa-mir-26a-2, hsa-mir-375, hsa-mir-328, hsa-mir-337, hsa-mir-338, hsa-mir-339, hsa-mir-384, hsa-mir-424, hsa-mir-429, hsa-mir-449a, hsa-mir-485, hsa-mir-146b, hsa-mir-494, hsa-mir-497, hsa-mir-498, hsa-mir-520a, hsa-mir-518f, hsa-mir-499a, hsa-mir-509-1, hsa-mir-574, hsa-mir-582, hsa-mir-606, hsa-mir-629, hsa-mir-449b, hsa-mir-449c, hsa-mir-509-2, hsa-mir-874, hsa-mir-744, hsa-mir-208b, hsa-mir-509-3, hsa-mir-1246, hsa-mir-1248, hsa-mir-219b, hsa-mir-203b, hsa-mir-499b
Targets of the most remarkably down-regulated miRNAs (let-7, miR-10, miR-26, miR-30, miR-34, miR-99, miR-122, miR-123, miR-124, miR-125, miR-140, miR-145, miR-146, miR-191, miR-192, miR-219, miR-222, and miR-223) regulate proliferation, gene expression, stress response, apoptosis, and angiogenesis. [score:9]
In addition to studies of T cells, a number of reports have examined peripheral blood mononuclear cells and have shown miR-192 downregulation in mild asthmatics [34] and miR-211 and miR-485-3p upregulation in pediatric patients with asthma [18, 20]. [score:7]
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[+] score: 15
In the up-regulated miRNAs, we found the five miRNAs have both 5p-arm and 3p-arm expression significantly increased (miR-146b, miR-200a, miR-141 miR-192 and miR-194). [score:6]
In Figure 3A, the utmost ten expressed miRNAs are miR-143, miR-148a, miR-21, miR-22, miR-375, miR-10a, miR-30a, miR-192, miR-99b and miR-145. [score:3]
The highly expressed miRNA genes (combined 5p-arm and 3p-arm together) in the STAD cancer group are: miR-21, miR-143, miR-22, miR-148a, miR-10a, miR-192, miR-375, miR-99b, let-7a-2 and miR-30a. [score:3]
Finally, we observe most of highly expressed miRNAs in both the normal and cancer STAD groups, including miR-143, miR-21, miR-22, miR-148a, miR-10a, miR-192, miR-375, miR-99b and miR-30a. [score:3]
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[+] score: 15
Specifically, the authors showed that miR-192 and miR-204 directly suppress HOTTIP in vitro and further identified the GLS1 gene, which plays a critical role in glutaminolysis and tumorigenesis, as a putative downstream target of HOTTIP. [score:6]
The role of miRNAs in HOTTIP regulation has been further unraveled by Ge et al., who observed a negative correlation between HOTTIP and miR-192/204 in 48 tumor-normal paired liver samples and showed that HOTTIP expression can be regulated by miR-192 and miR-204 via the canonical Argonaute2 mediated interference (siRNA) [136]. [score:5]
Ge Y. Yan X. Jin Y. Yang X. Yu X. Zhou L. Han S. Yuan Q. Yang M. Mirna-192 and mirna-204 directly suppress lncrna hottip and interrupt gls1 -mediated glutaminolysis in hepatocellular carcinomaPLoS Genet. [score:4]
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[+] score: 14
Smith et al. [11] demonstrated that miR-143, miR-145, and miR-205 expression levels appear to be elevated in oesophageal squamous mucosa of individuals with ulcerative oesophagitis, while Bus et al. [12] reported that miR-143, miR-145, miR-192, and miR-194 were upregulated in esophageal epithelial cells upon acidic bile salt stimulation. [score:6]
To assess differential expression of miRNAs in exfoliated cells of the tongue coating between GERD (n = 24) and Ctrls (n = 24), 6 candidate miRNAs (miR-143, miR-145, miR-192, miR-194, miR-203, and miR-205) were selected. [score:3]
In this study, we hypothesised that miR-143, miR-145, miR-192, miR-194, miR-203, and miR-205 expression might be altered in tongue coating in response to chronic gastroesophageal reflux. [score:3]
Subsequent research found that miR-143, miR-145, miR-192, and miR-194 were also significantly increased in esophageal epithelial cells (Het-1A) upon acidic bile salt stimulation [12]. [score:1]
We evaluated the expression levels of miR-143, miR-145, miR-192, miR-194, miR-203, and miR-205 in exfoliated cells of the tongue coating in patients with GERD and Ctrls across a discovery cohort of 48 specimens. [score:1]
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[+] score: 14
VEGF was reported to suppress EMT by inhibiting the expression of miR-192 [30], which increases E-cadherin levels via repressed translation of ZEB2 mRNA [31]. [score:9]
Ectopic expression of miR-192 and miR-215 increased E-cadherin levels by targeting ZEB2 [31]. [score:5]
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[+] score: 14
Another recent study shows that overexpressing proline-rich polypeptide (PRP-1) inhibited mTORC1, which resulted in upregulation of certain tumor suppressor miRNAs (miR-125b, miR-192) and downregulation of oncomiRs (miR-550, miR-589, miR-490-3p) (Galoian et al., 2014). [score:13]
Braun et al. found that miRNAs such as miR-192 and miR-215 are p53 responsive miRNAs that are capable of causing cell cycle arrest in the osteosarcoma cell line U2OS that carries a wild-type p53 (Braun et al., 2008). [score:1]
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[+] score: 13
The top five differentially upregulated miRNAs in cirrhosis (Table  1) were: miR-7704 (403-fold), miR-22 (143-fold), miR-101 (113-fold), miR-486 (75-fold), and miR-192 (32-fold). [score:4]
The top five differentially upregulated miRNAs in HGDN (Table  3) were: miR-101 (266-fold), miR-22 (170-fold), miR-16 (54-fold), miR-192 (45-fold), and miR-19b (34-fold). [score:4]
The top five differentially upregulated miRNAs in eHCC (Table  4) were: miR-101 (215-fold), miR-22 (94-fold), miR-10b (34-fold), miR-19b (34-fold), and miR-192 (29-fold). [score:4]
The sncRNAs most strongly associated with cirrhosis were mir-192 (32-fold), miR 320b (14-fold), and circ-0079763 (27-fold). [score:1]
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[+] score: 13
We discovered that of these five miRNAs, miR-122 and miR-192 were upregulated at least 1.5-fold in both HES1 and HES2 cells, while miR-135b and miR-33a were upregulated only in HES2 cells, and miR-224 was upregulated only in HES1 cells. [score:10]
Furthermore, induction of several liver-enriched miRNAs, including miR-122 and miR-192, was observed in parallel to induction of endodermal gene expression. [score:3]
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[+] score: 13
For example, miR-17-92 cluster are expressed on endothelial cells in addition to cardiomyocytes [40], and miR-296, miR-10b, miR-192 and miR-15a are also expressed on endothelial cells [41]. [score:5]
The remaining 14 (miR-18a-5p, miR-146a-5p, miR-30d-5p, miR-17-5p, miR-200a-3p, miR-19b-3p, miR-21-5p, miR-193-5p, miR-10b-5p, miR-15a-5p, miR-192-5p, miR-296-5p, miR-29a-3p, and miR-133a-3p) were upregulated in HCM patients with T [1] < 470 ms compared with those with T [1] ≥ 470 ms, and 11 (except miR-192-5p, miR-296-5p and miR-133a-3p) were significantly inversely correlated with postcontrast T [1] values. [score:3]
T [1] ≥ 470 ms Table 3Correlations between circulating miRNAs measured by miRNA array and T [1] times miRNA r P value miR-18a-5p −0.521 0.082 miR-146a-5p −0.658 0.020 miR-30d-5p −0.599 0.040 miR-17-5p −0.458 0.134 miR-200a-3p −0.436 0.157 miR-19b-3p −0.434 0.159 miR-21-5p −0.443 0.150 miR-193a-5p −0.553 0.062 miR-10b-5p −0.548 0.065 miR-15a-5p −0.475 0.119 miR-192-5p −0.512 0.089 miR-296-5p −0.557 0.060 miR-96-5p −0.579 0.049 miR-373-3p −0.517 0.085 Spearman correlation coefficients were computed to assess the correlations between postcontrast T1 times and miRNAs Validation of by real-time PCRWe validated the expression of the above 14 miRNAs plus miR-29a-3p and miR-133a-3p in all 55 HCM patients by. [score:1]
11 miRNAs were significantly and inversely correlated with postcontrast T [1] times, but the inverse correlations with T [1] times were not significant for miR-192-5p (r = 0.246, p = 0.071), miR-296-5p (r = 0.239, p = 0.079) and miR-133a-3p (r = −0.208, P = 0.127) (Fig.   3). [score:1]
T [1] ≥ 470 ms Table 3Correlations between circulating miRNAs measured by miRNA array and T [1] times miRNA r P value miR-18a-5p −0.521 0.082 miR-146a-5p −0.658 0.020 miR-30d-5p −0.599 0.040 miR-17-5p −0.458 0.134 miR-200a-3p −0.436 0.157 miR-19b-3p −0.434 0.159 miR-21-5p −0.443 0.150 miR-193a-5p −0.553 0.062 miR-10b-5p −0.548 0.065 miR-15a-5p −0.475 0.119 miR-192-5p −0.512 0.089 miR-296-5p −0.557 0.060 miR-96-5p −0.579 0.049 miR-373-3p −0.517 0.085 Spearman correlation coefficients were computed to assess the correlations between postcontrast T1 times and miRNAs We validated the expression of the above 14 miRNAs plus miR-29a-3p and miR-133a-3p in all 55 HCM patients by. [score:1]
miR-192 and miR-200a are involved in transforming growth factor (TGF)-β signaling [32, 33]. [score:1]
Epithelial-to-mesenchymal transition (EMT) is another mechanism mediated by miRNAs in myocardial fibrosis and miR-10b, miR-192 and miR-200a have a role in TGF-β -dependent EMT [32– 35]. [score:1]
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[+] score: 13
This hypothesis has been demonstrated by recent studies as follows: Jin et al. report that curcumin may inhibit proliferation and promote apoptosis of NSCLC cells via upregulation of miR-192-5p followed by inhibition of PI3K/Akt pathway [9]. [score:8]
The study of Ye et al. highlights the pro-apoptotic effects of curcumin depend on induction of miR-192-5p/215 followed by targeting X-linked inhibitor of apoptosis (XIAP) gene [10]. [score:5]
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[+] score: 12
The analysis for the KC animals compared to controls revealed that miR-150, miR-494, miR-138, miR-148a*, miR-216a, and miR-217 (p-value = 0.01) were significantly downregulated (Table 1), whereas, miR-146b, miR-205, miR-31, miR-192, and miR-21 (p-value = 0.01) were significantly upregulated (Table 2). [score:6]
We have shown that in tumor samples compared to normal samples, the majority of miRNAs (miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, Let-7b, Let-195 and miR-96) were downregulated, and few were upregulated (miR-146b, miR-205, miR-31, miR-192, miR-194 21, miR-379, miR-431, miR-541, and miR-199b). [score:6]
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[+] score: 12
miRNAs have been associated with and put forth as putative biomarkers of human disease, including hepatitis C (miR-122) [6], cardiovascular diseases (miR-192) [7] and various types of cancers [8]. [score:5]
In contrast, the findings presented in this dog atlas show that cfa-miR-192 was expressed at relatively high levels (>650 RPM) in all tissues. [score:3]
Kidney enriched miR-10a and miR-192 were previously identified as potential circulating biomarkers of renal injury in rats [48], however miR-192 had high expression in multiple dog tissues and was not identified as kidney enriched in the current study. [score:3]
Others have reported miR-192 as a liver specific biomarker in multiple species [9, 20]. [score:1]
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[+] score: 12
In a mouse mo del of diabetic nephropathy, inhibition of miR-21 improved kidney function and alleviated the progression of renal injury [42], whereas inhibition of renal miR-192 suppressed the expression of fibrotic markers, such as collagen, TGF-β1, and fibronectin in a mouse mo del of type I diabetes nephropathy [43]. [score:9]
Putta S Lanting L Sun G Lawson G Kato M Natarajan R Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathyJ Am Soc Nephrol. [score:3]
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[+] score: 11
The most representative ones were miR-212, miR-026a, miR-150, miR-152, miR-191, and miR-192, which were upregulated in pituitary adenomas, while miR-024-1 and miR-098 were downregulated in tumor samples. [score:7]
Study of Cheng et al. suggested that the upregulated miR-150, miR-152, miR-191, and miR-192 may also be involved in apoptosis [84]. [score:4]
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53
[+] score: 11
It should be noted that other microRNAs potentially regulating CCNE1 protein expression were also significantly changed, including down-regulation of miR-141, miR-16, miR-15a, miR-352, miR-15b and up-regulation of miR-518e, miR-29a, miR-192, and miR-29b, implicating a regulatory network fine-tuning the cell cycle checkpoints. [score:11]
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[+] score: 11
For example, Pichiorri et al. [83] identified that in multiple myeloma, three miRNAs (miR-192, miR-194 and miR-215) are transcriptionally activated by p53 to suppress Mdm2 expression via directly binding to its mRNA, thereby protecting p53 from degradation. [score:6]
100, 101 In addition, p53-regulated miRNAs miR-200 and miR-192 are critical mediators of p53-regulated EMT, supported by the observation that these miRNAs are transactivated by p53 and modulate EMT program via repressing ZEB1/2 expression. [score:5]
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[+] score: 10
In the mouse mo del of renal fibrosis, ZEB1, which is a target of microRNA 192 (miR-192), was found to repress the expression of collagen 13. [score:5]
Inhibition of miR-192 increased ZEB1 and decreased collagen, inhibiting renal fibrosis 13. [score:5]
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[+] score: 10
Hepatic expression of tumor suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22 and miR-125b, and tumor promoting miRNAs, miR-10b and miR-99b in NASH-HCC mo del male and female mice. [score:5]
As shown in Fig. 4, the tumor suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22, and miR-125b were lower, whereas the tumor-promoting miRNAs, miR-10b and miR-99b were higher in males than in females in both the STZ-HFD group and the control group. [score:3]
We also observed that tumor-suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22, and miR-125b were significantly decreased in STZ-HFD mice compared to controls with significantly lower levels in males than in females. [score:2]
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[+] score: 10
As expected, general inflammation -associated miRNAs are differentially expressed in active disease, such as miR-146a (involved in innate Toll-like receptor (TLR) responses[15]), miR-192 (highly expressed in colonic tissues with active UC[16]), and miR-21 (upregulated in intestinal tissues of IBD patients[17]). [score:10]
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[+] score: 10
Kato and co-workers [10] reported on the expression and function of miR-192 in diabetic kidney glomeruli. [score:3]
This result was further validated using a TaqMan probe -based qRT-PCR, we detected the expression of miR-10a, miR-30d and miR-192 in various mouse organs: the heart, spleen, kidney, colon and lung. [score:3]
Although miR-192 was detected at a high level in the kidney, it was also strongly expressed in the liver and colon. [score:3]
When studying the serum and urinary levels of the miR-200 family, miR-205 and miR-192 in patients with systemic lupus erythematosus (SLE), Wang et al. [20] found that the levels of most of those miRNAs from patients were lower than the levels of controls, suggesting that miRNA may take part in the pathogenesis of SLE and that miRNAs in the urine and serum could be biomarkers for SLE. [score:1]
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[+] score: 10
MiR-92 was reported to play a regulated role in the proliferation of myeloid cells [42], while miR-192 suppressed cell proliferation and induced apoptosis. [score:4]
The expression levels of mfi-miR-192, mfi-miR-26, mfi-miR-143, mfi-miR-148a, mfi-miR-205a, mfi-miR-22-3p, mfi-miR-181a-5p, mfi-miR-182-5p, mfi-miR-194, mfi-miR-200a, mfi-miR-92a, and mfi-let-7f were highest in this study, implying their potential significant functions in M. fissipes metamorphosis. [score:3]
Among the miRNAs with high abundance (more than 100,000 counts), 12 miRNAs (mfi-miR-192, mfi-miR-26, mfi-miR-143, mfi-miR-148a, mfi-miR-205a, mfi-miR-22-3p, mfi-miR-181a-5p, mfi-miR-182-5p, mfi-miR-194, mfi-miR-200a, mfi-miR-92a, and mfi-let-7f) were most highly expressed in M. fissipes metamorphosis. [score:3]
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60
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Recently, several miRNAs, including miR-143/145, miR-192/194, miR-339–5p and miR-509-5p have been identified to regulate p53 levels and function through directly targeting MDM2 [27, 29, 30, 48, 49]. [score:5]
miR-192/194 are down-regulated in multiple myeloma [48]. [score:4]
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61
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In NSCLC tissues, many onco-miRs/tumor suppressor-target or tumor suppressor-miRs/onco-target pathways have been demonstrated to participate in the tumorigenesis of lung cancer, including miR7/BCL2 axis, miR-99b/FGFR3 axis, miR-101/EZH2 axis, miR-192/RB1 axis and miR-196/HOXA5 axis [26- 30]. [score:9]
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42) 13 hsa-mir-199b dbDEMC, HMDD, miR2Disease 38 hsa-mir-206 dbDEMC 14 hsa-mir-181a dbDEMC, miR2Disease 39 hsa-mir-192 dbDEMC 15 hsa-mir-29a dbDEMC, HMDD, miR2Disease 40 hsa-mir-335 literature 16 hsa-let-7e dbDEMC 41 hsa-mir-365 literature 17 hsa-mir-107 HMDD 42 hsa-mir-30a miR2Disease 18 hsa-mir-18a higher RWRMDA (No. [score:9]
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For example, miR-105 has been reported to function as a potential tumor suppressor and inhibit cell proliferation by regulating the PI3K/AKT signaling pathway in human HCC [11]; Tan and colleagues identified a serum of miRNA panel (hsa-miR-206, hsa-miR-141-3p, hsa-miR-433-3p, hsa-miR-1228-5p, hsa-miR-199a-5p, hsa-miR-122-5p, hsa-miR-192-5p, and hsa-miR-26a-5p) that has considerable clinical value in HCC diagnosis [12]; The presence of miR-101 has also been indicated to be a biochemical marker for monitoring the progression of tumor development in HBV-related HCC, and to be a potential prognostic marker and therapeutic target for HCC [13]. [score:9]
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64
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Previously, it was reported that p53, another well-known tumor suppressor, upregulates the transcription of tumor-suppressor miRNAs such as miR-34a/b/c/, miR-107, miR-145, miR-192, and miR-215, which regulate cell proliferation, apoptosis, and angiogenesis [29]. [score:9]
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65
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microRNA-192, -194 and -215 are frequently downregulated in colorectal cancer. [score:4]
miR-192/miR-215 influence 5-fluorouracil resistance through cell cycle -mediated mechanisms complementary to its post-transcriptional thymidilate synthase regulation. [score:2]
MiR-215 (and the related miR-192), functions in part by regulating cell cycle genes and by repressing cell proliferation (Boni et al., 2010; Fesler et al., 2015; Jones et al., 2015). [score:2]
This is consistent with the prognostic features of miR-192 (Chiang et al., 2012) and miR-215 (Karaayvaz et al., 2011; Faltejskova et al., 2012; Chiang et al., 2012; Li et al., 2013b), which are both depleted in CRC tumors. [score:1]
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66
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A previous study of an adult liver reported high expression of miR-122 and miR-194, and moderate expression of miR-148 and miR-192 [17], which is similar to our study (Fig. 5), indicating that these liver-specific miRNAs are important for the two developmental stages of the liver. [score:6]
However, the other three liver-specific miRNAs (miR-148, miR192 and miR-194) exhibited moderate expression levels (Fig. 5). [score:3]
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67
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More interestingly, a recent study has shown that miRNA192 were upregulated by TGF- β 1 in mouse mesangial cells, and miRNA192 plays a pivotal role in diabetic nephropathy, mediated via controlling TGF-β1 -induced collagen I expression by downregulating E-box repressors [14]. [score:9]
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68
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Hoogendoorn et al. (2012) also detected PM effects on the expression of some of the miRNA target genes observed in our study, such as the proliferation- and carcinogen-related genes E2F1, EGR1 targeted by hsa-miR-21 and hsa-miR-192, and the inflammation-related gene NFKB1 targeted by miR-146a. [score:9]
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69
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7e, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-20a, hsa-mir-21, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-101-1, hsa-mir-106a, hsa-mir-107, hsa-mir-34a, hsa-mir-204, hsa-mir-205, hsa-mir-214, hsa-mir-215, hsa-mir-222, hsa-mir-223, hsa-mir-1-2, hsa-mir-15b, hsa-mir-125b-1, hsa-mir-141, hsa-mir-191, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-149, hsa-mir-184, hsa-mir-186, hsa-mir-200c, hsa-mir-1-1, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-339, hsa-mir-146b, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-624, hsa-mir-650, hsa-mir-651, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-449b, hsa-mir-1185-2, hsa-mir-1283-1, hsa-mir-1185-1, hsa-mir-708, hsa-mir-548e, hsa-mir-548j, hsa-mir-1285-1, hsa-mir-1285-2, 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-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-1283-2, hsa-mir-548q, hsa-mir-548s, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-548x, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-548am, hsa-mir-548an, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-548ay, hsa-mir-548az, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
These microRNAs, that included miR-15b, miR-205, miR-34a, miR-34c, miR-192, miR-200a and miR-107 target p53 inhibitors (such as MDM2), cell cycle genes (CDK4/6, E2F, CCNE1/2, CDC7), oncogenes (MET), growth factors (IGF1), antiapoptotic genes (BCL2), metabolic genes (LDHA), stemness genes (NANOG, SOX2, KLF4, OCT4, CD44), proangiogenic genes (ANRT) [27– 29] or genes involved in proliferation and metastasis (LAMC1). [score:5]
Finally, The MDM-blocking miRNA miR-192 was down-regulated (Fig 5). [score:4]
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70
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The expression pattern of 12 specific upregulated miRNAs (miR-17-3p, miR-21, miR-106a, miR-146, miR-155, miR-191, miR-192, miR-203, miR-205, miR-210, miR-212, miR-214) in tumor samples was similar in the tumor plasma-derived exosomes and distinct from the control samples, indicating exosomal miRNAs could be relevant as a screening method for this tumor (122). [score:6]
In a recent study, Valencia et al demonstrated that the exosomal miR-192 derived from lung adenocarcinoma cell lines repressed the angiogenic activity in the co-cultured endothelial cells by the inhibition of the proangiogenic factors (112). [score:3]
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71
[+] score: 8
Using microarrays, we previously showed that 6 of 52 miRNAs were differentially expressed more than two fold in docetaxel-resistant SPC-A1/DTX cells compared with parental SPC-A1 cells, including three upregulated miRNAs (miR-192, miR-424 and miR-98) and three downregulated miRNAs (miR-200b, miR-194 and miR-212) [16]. [score:8]
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72
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Expression levels of fru-miR-196a-5p, fru-miR-206-3p, fru-miR-194-5p, fru-miR-192-5p, and fru-miR-10b-5p in slow muscle were 1305-, 529-, 93-, 85-, and 77-fold higher, respectively, compared with cardiac muscle, while expression levels of fru-miR-187-3p, fru-miR-30e-3p, fru-miR-140-3p, fru-miR-218a-5p, and fru-miR-140-5p were 16-, 16-, 10-, 8-, and 6-fold higher, respectively, in cardiac muscle compared with slow muscle. [score:3]
However, for fru-miR-499-5p, fru-miR-192-5p, fru-miR-196a-5p, fru-miR-202-5p (data not shown) and fru-miR-2478-3p, the results from q-PCR were not consistent with the sequencing results. [score:1]
miR-192-5p belongs to the miR-192/215 family [10]. [score:1]
For example, fru-miR-1-3p was muscle specific, fru-miR-196a-5p was skeletal muscle specific, fru-miR-499-5p was heart and slow muscle specific, fru-miR-204-5p was eye specific, fru-miR-9-3p was brain and eye specific, fru-miR-192-5p was intestine and liver specific, fru-miR-122-5p was liver specific, and fru-miR-202-5p was ovary specific. [score:1]
Fru-miR-192-5p was the most abundant miRNA in the intestine. [score:1]
miR-192 and miR-215 share identical seed sequences, and only differ by two nucleotides [10]. [score:1]
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73
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miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms. [score:8]
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74
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The group II shown in Figure 5 included two subgroups with similar expression patterns, in that miRNAs in the first subgroup (miR-192 and miR-194, r = 0.988) had rather focused expression in the gastrointestinal organs as well as in kidney. [score:5]
A neighboring group of miRNAs (miR-192, miR-194, and miR-215) shared similar expression patterns but particularly in the gastrointestinal organs (r = 0.912, Figure 2). [score:3]
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75
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Nagel et al. [115] using a forward genetics screening approach, in combination with a variety of luciferase -based transfection studies, showed that the miRNA-192/194 gene cluster negatively regulates expression of per1-3. Overexpression of these miRNAs caused a decrease in circadian period length, possibly through dampening per expression. [score:8]
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76
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Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathway. [score:8]
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77
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Two nucleotide excision repair (NER) factors, ERCC3 and ERCC4, have been demonstrated to be modulated by miR-192 and overexpression of miR-192 significantly inhibited cellular NER ultimately leading to HCC [34]. [score:5]
Next, to further explore the functions of these miRNAs in HCC, we selected miRNAs with a fold change >5, namely hsa-miR-636, hsa-miR-671, hsa-miR-489, hsa-miR-26a, hsa-miR-320, hsa-miR-628, hsa-miR-505, hsa-miR-100, hsa-miR-664, hsa-miR-942, hsa-miR-192, hsa-miR-99b, hsa-miR-125b, hsa-miR-10b, hsa-miR-30b, and hsa-miR-145, for GO (Gene Ontology) enrichment analysis [21] of their target genes using the web -based software WebGestalt 2.0 [22]. [score:3]
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78
[+] score: 8
Moreover, miR-192 is reported to suppress metastasis of CRC [46] and its synthesis, along with that of miR-215 (also highly represented in our 254 miRNA dataset), is induced by p53 and shown to play an important regulatory role of genes involved in the TGF-β signalling pathway [47], [48]. [score:4]
Of these, miR-192-5p, miR-10a-5p and miR-191-5p are the most highly represented our dataset along with members of the let-7 and miR-8 families. [score:1]
This analysis revealed the prominence in all three EVs of members from the following families: let-7 (12/12 members observed, let-7a/b/c/d/e/f/g/i, miR-98-5p), miR-181 (6/6, miR-181a-1/a-2/b-1/b-2/c/d), miR-30 (6/6, miR-30a/b/c-1/c-2/d/e), miR-320 (7/8, miR-320a/b-1/b-2/c-1/c-2/d-1/d-2), miR-8 (5/5, miR-141, miR-200a/b/c and miR-429), miR-17 (6/8, miR-106a/b, miR-17, miR-18a, miR-20a and miR-93), miR-192 (2/2, miR-192 and miR-215) and miR-25 (3/4, mir-25 and mir-92a/b). [score:1]
For example, miR-192 has been observed in tissue [41] and serum/plasma [42] from CRC patients, miR-191 in tissue [41], [43] and serum/plasma [44], and miR-10a in tissue [45] and serum/plasma [42] from CRC patients. [score:1]
Interestingly, the top three most highly-represented miRNAs identified in LIM1863-derived EVs - miR-192-5p, miR-10a-5p, and miR-191-5p - have been reported previously in tissue and serum of CRC patients as potential diagnostic biomarkers. [score:1]
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The expression of tissue specific miRNAs is often regulated at the transcription level by tissue specific transcription factors (for examples, miR-122a by HNF4, miR-192 and miR-194 by HNF1 [8], [9]. [score:4]
Similarly, genes encoding for miR-192 and miR-194 are clustered on chromosome 1, and could explain their coordinated increase in expression (Table 2). [score:3]
Similarly, the binding site of a liver specific transcription factor HNF-1 can be predicted in the 5′ upstream region of miR-122a, miR-192 and miR-194-2 [9], [27], [36]. [score:1]
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80
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-210, hsa-mir-215, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-138-2, hsa-mir-143, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-138-1, hsa-mir-146a, hsa-mir-193a, hsa-mir-194-1, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-194-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-302a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-369, hsa-mir-371a, hsa-mir-340, hsa-mir-335, hsa-mir-133b, hsa-mir-146b, hsa-mir-519e, hsa-mir-519c, hsa-mir-519b, hsa-mir-519d, hsa-mir-519a-1, hsa-mir-519a-2, hsa-mir-499a, hsa-mir-504, hsa-mir-421, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-190b, hsa-mir-301b, hsa-mir-302e, hsa-mir-302f, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-320e, hsa-mir-371b, hsa-mir-499b
The action of p53 is also essential for induction of the related miRNAs miR-192, miR-194 and miR-215, which are up-regulated by genotoxic stress and are capable of inducing cell cycle arrest by causing increased expression of multiple transcripts involved in S phase and G1 and G2 checkpoints in human colon cancer samples [21] and human osteosarcoma cells [22]. [score:6]
Georges S. A. Biery M. C. Kim S. Y. Schelter J. M. Guo J. Chang A. N. Jackson A. L. Carleton M. O. Linsley P. S. Cleary M. A. Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215 Cancer Res. [score:2]
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81
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miR-21 was shown to suppress PTEN, a key modulator in DN [67]; miR-192 was shown to suppress ZEB2, which is responsible for controlling TGF-β -induced extracellular matrix proteins accumulating during DN [67], while miR-29c was shown to inhibit SPRY1, which involves albuminuria and kidney mesangial matrix accumulation in diabetic mice mo dels [68]. [score:7]
Recently, a prospective case-control study showed that miR-21, miR-29a/b/c, and miR-192 reflect DN pathogenesis and could be of clinical significance to monitor and prevent DN advancement [66]. [score:1]
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82
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Later, Remco et al. identified the miR-192 ⁄ 194 cluster as a potent inhibitor of the entire Period gene family using a forward genetic screen, unveiling a new mechanism for the downregulation of the circadian clock genes at the post-transcriptional level [35]. [score:6]
It suggests that other factors rather than miR-192⁄194 cluster may be responsible for the hPer2 gene deregulation in CRC progression. [score:2]
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83
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Activation of tumor suppressor p53 can induce miR-194 and its clustered miR-192 and miR-215 expression [55], [57]. [score:5]
Ann Surg Oncol 57 Georges SA Biery MC Kim SY Schelter JM Guo J 2008 Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. [score:2]
miR-192 and miR-215 can induce p21Cip1 and cell cycle arrest in colon cancer cells [55]. [score:1]
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84
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Pichiorri et al. observed that the ectopic expression of miRNA-192, -194 and -215 induced significant down-regulation of MDM2 that was accompanied by p53 overexpression and p21 activation [97]. [score:8]
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85
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7e, hsa-mir-15a, hsa-mir-16-1, 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-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-99a, hsa-mir-100, hsa-mir-101-1, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-16-2, hsa-mir-196a-1, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-10a, hsa-mir-196a-2, hsa-mir-199a-2, hsa-mir-203a, hsa-mir-215, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-200b, hsa-mir-1-2, hsa-mir-15b, hsa-mir-27b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-141, hsa-mir-143, hsa-mir-145, hsa-mir-152, hsa-mir-191, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-146a, hsa-mir-150, hsa-mir-185, hsa-mir-194-1, hsa-mir-195, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-128-2, hsa-mir-194-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-130b, hsa-mir-302c, hsa-mir-375, hsa-mir-378a, hsa-mir-148b, hsa-mir-324, hsa-mir-451a, hsa-mir-483, hsa-mir-484, hsa-mir-486-1, hsa-mir-500a, hsa-mir-92b, hsa-mir-595, hsa-mir-596, hsa-mir-421, hsa-mir-378d-2, hsa-mir-744, hsa-mir-885, hsa-mir-939, hsa-mir-940, hsa-mir-1229, hsa-mir-1233-1, hsa-mir-1290, hsa-mir-1246, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-718, hsa-mir-378b, hsa-mir-378c, hsa-mir-4306, hsa-mir-4286, hsa-mir-500b, hsa-mir-1233-2, hsa-mir-3935, hsa-mir-642b, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-3976, hsa-mir-4644, hsa-mir-203b, hsa-mir-451b, hsa-mir-378j, hsa-mir-486-2
They identified a correlation between high miR-192 and miR-222 expression levels and a high T-category, and also showed that miR-302c and miR-222 expression levels correlated with OS [76]. [score:5]
Several circulating miRNAs were identified as biomarkers for the detection and diagnosis of GC: miR-21, miR-200c, miR-421, miR-199a, miR-122, miR-192, miR-222, miR-16, miR-25, miR-92a, miR-451, miR-486-5p, miR-940, miR-223, miR-19b, miR-194, miR-141, and miR-1233, with a reasonable degree of diagnostic ability [25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. [score:1]
Several groups identified circulating miRNAs, such as miR-19a, miR-195, miR-192, miR-146a, miR-148, miR-152, miR-122 and let-7b, miR-18a, miR-100, miR-145 miR-223 miR-200a, and miR-222, as non-invasive markers for discriminating HCC from other hepatic disorder statuses [56, 57, 58, 59, 60, 61]. [score:1]
Chen Q. Ge X. Zhang Y. Xia H. Yuan D. Tang Q. Chen L. Pang X. Leng W. Bi F. Plasma miR-122 and miR-192 as potential novel biomarkers for the early detection of distant metastasis of gastric cancer Oncol. [score:1]
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86
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Next, the expression of four endogenous miRNAs (miR-122, miR-192, miR-21 and miR-16) was analyzed by qPCR, showing that the detection of the analyzed targets sequence is linear (as shown by the linear regression R [2]). [score:5]
Microarray analysis identified a panel of miRNAs, which are either highly expressed in the heart (miR-1, miR-133a and miR-16) or in the liver (miR-122, miR-192 and miR-194) or invariant (miR-21; Supplementary Figure 1a). [score:3]
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87
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Kinases and transcription factors important in immune-cell differentiation and regulation such as Blimp-1 51, p53/MDM2 52 and PTEN 53 may be targets of miR-30a, miR-30d, miR-192 and miR26a, all CIR-miRNAs downregulated in sepsis, in our study. [score:7]
A combination of top 5 significantly different CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p and miR-23a-5p) was sufficient to achieve discrimination of severe sepsis from non-infective SIRS patients (Fig. 3C). [score:1]
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88
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IsomiRs of miR-192-5p display more expanded or restricted expression with respect to tissues. [score:3]
IsomiRs in other tissues such as isomiRs of miR-215 in the intestine (Additional file 11: Figure S3), miR-192-5p in the liver (Additional file 12: Figure S4) and miR-3473f-pre in the testis (Additional file 13: Figure S5 and Additional file 14: Figure S6) display similar isomiR expression. [score:3]
IsomiRs of miR-192-5p in the liver. [score:1]
Additionally, miR-122 and liver enriched miR-192 were increased in the serum of patients who had acetaminophen induced hepatotoxicity demonstrating the potential for these miRNAs to be used as both preclinical and clinical biomarkers for liver injury [24]. [score:1]
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89
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For instance, downregulation of miR200b, -194 and -212 and upregulation of miR192, -424 and -98 are associated with docetaxel resistance in non small cell lung carcinoma [80]. [score:7]
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90
[+] score: 7
The genome-wide microarray screening study identified a group of miRNAs differentially expressed in active UC in the American population, including 3 downregulated miRNAs (miR-192, miR-375 and miR-422b) and 8 unregulated miRNAs (miR-16, miR-21, miR-23a, miR-24, miR-29a, miR-126, miR-195 and Let-7f) in the colons of active UC patients [18]. [score:7]
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91
[+] score: 7
In GC, miR-192, miR-215, miR-25 are reported to be upregulated, whereas miR-375, miR-101 are downregulated [9– 12]. [score:7]
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92
[+] score: 7
Collectively, these observations highlight a potential relationship between miR-21 and TGF-β1, possibly via SMAD7, that could drive fibrogenesis in chronic hepatitis C. Moreover, miR-192 increased by HCV infection can directly upregulate TGF-β1 expression, suggesting that it is also as a major factor mediating HCV infection -associated fibrogenesis [44]. [score:7]
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93
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Both expression of miR-192 and miR-200b were greatly reduced in the conditional Dgcr8 knockout mouse line (Figure  2). [score:4]
Both expression of miR-192 and miR-200b is strongly reduced in Dgcr8 knockout kidneys when compared to WT littermates (4-7 week old animals; ** = p < 0.01; error bars represent SEM). [score:3]
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94
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The expression of miR-23a, miR-181c, miR-192, miR-194, miR-208, miR-337-5p, miR-338-3p, miR-502-5p, miR-542-3p, miR-628-5p, and miR-672 is upregulated in the oral mucosa of heavy smokers with lung cancer versus patients without cancer and light smokers [66]. [score:6]
A microarray analysis of exosomes in alcohol -treated mice versus controls showed that miR-192, miR-122, and miR-30a differentiate alcohol -induced liver injury in mice and humans with excellent diagnostic accuracy [102]. [score:1]
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95
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The miRNAs downregulated the most included the miR-141/miR-200 and miR-30 families, as well as miR-192, miR-204, and miR-215, which play key roles in maintaining epithelial cell phenotype [17, 18], and their downregulation is in accordance with the EMT-like change occurring in cultured BCD cells. [score:7]
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96
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Interestingly, when assessing miR-192 in human DN kidney, expression levels not only are reduced but also inversely correlate with severity of kidney disease [72], raising once again the issue about the appropriateness of the currently available animal mo dels for DN. [score:5]
Initially identified in a mice mo del of DN, miR-192, along with miR-377, miR-337, and miR-129, was later discovered as being enriched in human mesangial cells (MCs) exposed to high glucose [67]. [score:1]
The first miRNA to be recognized as relevant contributor to DN progression was miR-192 [109]. [score:1]
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97
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Finally, miR-192 was observed in different studies to be up-regulated in tissue in animal mo del of fibrosis, but down-regulated in human tissue samples and increased in human urine samples [66– 69]. [score:7]
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98
[+] 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-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-99a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-99a, mmu-mir-140, mmu-mir-10b, mmu-mir-181a-2, mmu-mir-24-1, mmu-mir-191, hsa-mir-148a, hsa-mir-30d, mmu-mir-122, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-122, hsa-mir-140, hsa-mir-191, hsa-mir-320a, mmu-mir-30d, mmu-mir-148a, mmu-mir-192, 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-21a, mmu-mir-22, mmu-mir-24-2, mmu-mir-26a-1, mmu-mir-92a-2, mmu-mir-25, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-92a-1, hsa-mir-26a-2, hsa-mir-423, hsa-mir-451a, mmu-mir-451a, hsa-mir-486-1, mmu-mir-486a, mmu-mir-423, bta-mir-26a-2, bta-let-7f-2, bta-mir-148a, bta-mir-21, bta-mir-30d, bta-mir-320a-2, bta-mir-99a, bta-mir-181a-2, bta-mir-27b, bta-mir-140, bta-mir-92a-2, bta-let-7d, bta-mir-191, bta-mir-192, bta-mir-22, bta-mir-423, bta-let-7g, bta-mir-10b, bta-mir-24-2, bta-let-7a-1, bta-let-7f-1, bta-mir-122, bta-let-7i, bta-mir-25, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, hsa-mir-1246, bta-mir-24-1, bta-mir-26a-1, bta-mir-451, bta-mir-486, bta-mir-92a-1, bta-mir-181a-1, bta-mir-320a-1, mmu-mir-486b, hsa-mir-451b, bta-mir-1246, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2
Several microRNAs had similar expression when comparing results from the present study with those of There were nine microRNAs (bta-miR-10b, bta-miR-423-3p, bta-miR-99a-5p, bta-miR-181a, bta-miR-423-5p, bta-miR-148a, bta-miR-26a, bta-miR-192, and bta-miR-486), that were upregulated in earlier stages of life in both studies. [score:6]
Bta-miR-320a and bta-miR-192 had the greatest number of copies during fall, 2013, while spring, 2014, had the fewest (P< 0.02). [score:1]
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99
[+] score: 7
Other miRNAs from this paper: hsa-mir-200b, hsa-mir-200a, hsa-mir-377
miR-192 and miR-377, both upregulated by TGF-β1 in mesangial cells, are hyper-expressed in mouse mo dels of diabetic nephropathy [41, 42]. [score:6]
Also, a loss of miR-192 has been associated with fibrogenesis in humans [44]. [score:1]
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100
[+] score: 7
b. Wild-type p53 represses cancer initiation, progression and metastasis by regulating downstream genes and microRNAs (miR-34, miR-130b, miR-192 and miR-200c)-target gene networks. [score:4]
Emerging evidence has demonstrated that WT p53 can also indirectly silence EMT-inducing transcription factors though the transcriptional regulation of some miRNAs, such as miR-34, miR-130b, miR-145, miR-192, miR-215 and miR-200c [21, 22, 23, 24, 25, 26, 27]. [score:3]
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