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Circulating microRNAs associated with liver fibrosis in chronic hepatitis C patients

ABSTRACT: In this study, we compared circulating miRNAs identified in hepatitis C virus (HCV)-infected patients presenting two extremes of liver disease: mild/moderate fibrosis and cirrhosis. The patients in the cirrhosis group subsequently developed hepatocellular carcinoma (HCC). Methods: Expression profile of miRNA were identify by semiconductor sequencing using Ion Proton High Power Sequencer. The sequences were exported in FASTQ format for further analysis using the CLC Genomics Workbench software version 8.5. The transcripts were trimmed and then annotated by comparing sequence similarity to miRBASE. After identification of mature miRNAs, differential expression analysis of miRNAs between the mild fibrosis and cirrhosis groups was performed using Empirical Analysis of Differential Gene Expression (EDGE). To verify the potential target genes regulated by the differentially expressed miRNAs identified between the two groups studied, the miRnet tool version 2.0 was applied to identify the regulatory networks in which the miRNAs are involved. Results: We identified 163 mature miRNAs in the mild/moderate fibrosis group and 171 in the cirrhosis group, with 144 in common to both groups. Differential expression analysis revealed 5 upregulated miRNAs and 2 downregulated miRNAs in the cirrhosis group relative to the mild/moderate fibrosis group. Functional analyses of regulatory networks (target gene and miRNA) identified gene categories involved in cell cycle biological processes and metabolic pathways related to cell cycle, cancer, and apoptosis. Conclusion:These results suggest that the differentially expressed circulating miRNAs observed in this work (miR-215-5p, miR-483-5p, miR-193b-3p, miR-34a-5p, miR-885-5p, miR-26b-5p and miR -197-3p) may be candidates for biomarkers in the prognosis of liver disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160879 | GEO | 2020/11/06

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are a class of highly conserved endogenous noncoding single-stranded small RNAs with a length of 18-22 nucleotides. They are involved in regulation at the posttranscriptional and translational levels through the degradation and translation inhibition of messenger RNA (mRNA). It is estimated that at least 60% of all mammalian genes may be regulated by miRNAs. MiRNAs can help uncover the mechanisms of diseases and provide new entry points into therapy. Accumulated evidence has revealed that miRNAs are involved in the pathological process of cardiovascular disease through specific signaling pathways. To investigate the potential miRNAs for myocardial fibrosis post myocardial infarction, rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. There were three rats in each group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3β. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3β was decreased in CFs transfected with miR-199a-5p mimics. In summary, our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3β, which provides novel targets for diagnosis and treatment of MF. In summary, our research suggests that miR-199a-5p promotes the progression of myocardial fibrosis after myocardial infarction through the activation of the insulin-PI3K/Akt-GSK-3β signaling pathway.

Project description:We tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, −542-3p, and −671-5p all increased following treatment of Ishikawa cells with progesterone (10 μg/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.

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Circulating microRNAs associated with liver fibrosis in chronic hepatitis C patients

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