Identification of miRNA-target gene regulatory networks in liver fibrosis based on bioinformatics analysis

Abstract

Background Liver cirrhosis is one of the leading causes of death worldwide. MicroRNAs (miRNAs) can regulate liver fibrosis, but the underlying mechanisms are not fully understood, and the interactions between miRNAs and mRNAs are not clearly elucidated. Methods miRNA and mRNA expression arrays of cirrhotic samples and control samples were acquired from the Gene Expression Omnibus database. miRNA-mRNA integrated analysis, functional enrichment analysis and protein-protein interaction (PPI) network construction were performed to identify differentially expressed miRNAs (DEMs) and mRNAs (DEGs), miRNA-mRNA interaction networks, enriched pathways and hub genes. Finally, the results were validated with in vitro cell models. Results By bioinformatics analysis, we identified 13 DEMs between cirrhotic samples and control samples. Among these DEMs, six upregulated (hsa-miR-146b-5p, hsa-miR-150-5p, hsa-miR-224-3p, hsa-miR-3135b, hsa-miR-3195, and hsa-miR-4725-3p) and seven downregulated (hsa-miR-1234-3p, hsa-miR-30b-3p, hsa-miR-3162-3p, hsa-miR-548aj-3p, hsa-miR-548x-3p, hsa-miR-548z, and hsa-miR-890) miRNAs were further validated in activated LX2 cells. miRNA-mRNA interaction networks revealed a total of 361 miRNA-mRNA pairs between 13 miRNAs and 245 corresponding target genes. Moreover, PPI network analysis revealed the top 20 hub genes, including COL1A1, FBN1 and TIMP3, which were involved in extracellular matrix (ECM) organization; CCL5, CXCL9, CXCL12, LCK and CD24, which participated in the immune response; and CDH1, PECAM1, SELL and CAV1, which regulated cell adhesion. Functional enrichment analysis of all DEGs as well as hub genes showed similar results, as ECM-associated pathways, cell surface interaction and adhesion, and immune response were significantly enriched in both analyses. Conclusions We identified 13 differentially expressed miRNAs as potential biomarkers of liver cirrhosis. Moreover, we identified 361 regulatory pairs of miRNA-mRNA and 20 hub genes in liver cirrhosis, most of which were involved in collagen and ECM components, immune response, and cell adhesion. These results would provide novel mechanistic insights into the pathogenesis of liver cirrhosis and identify candidate targets for its treatment.

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

“…Wang et al [715], Lu et al [716], Shi et al [717], Yu et al [718], Zhang et al [719] and Ren et al [720] reported that altered expression of hsa-mir-3613-3p, hsa-mir-103a-3p, hsa-mir-150-5p, GATA2, RUNX1 and AHR (aryl hydrocarbon receptor) correlated in patients with kidney disease, but these genes might be novel targets for NAFLD. Previous reports have demonstrated that hsa-mir-150-5p [721] and RUNX1 [722] are associated with liver cirrhosis.…”

Exploration of the core pathway of inflammatory bowel disease complicated with metabolic fatty liver and two-sample Mendelian randomization study of the causal relationships behind the disease

“…Among the miRNAs shared by IBD and NAFLD identified in this study, hsa-miR-122-5p has been reported to be a serum marker for the diagnosis of NAFLD ( 61 ), while has-miR-146b-5p is associated with different subtypes of UC ( 62 ). At the same time, hsa-miR-150-5p and hsa-Mir-150-5p were used as the related miRNAs of liver fibrosis ( 63 ). We speculate that has-miR-146b-5p may play a role in the pathogenesis of IBD combined with NAFLD, but this needs to be confirmed by further studies.…”

Comprehensive Analysis of Differentially Expressed Circular RNAs in Keloid Dermal Tissues

“…As we know, the keloid is associated with sex hormone levels, which suggested that expression levels of hsa_circ_0072688 might be regulated by sex hormones. Among miRNAs in the hsa_circ_0072688-centered ceRNA networks, dysregulation of the-miR-146a-5p[38], has-miR-146b-5p [39], hsa-miR-373-3p [40], and hsa-miR-93-5p [41] were reported in organ brosis. KEGG and GO enrichment analysis results demonstrated that hsa_circ_0072688 is related to the extracellular matrix, cell adhesion, cell apoptosis, and stress ber, and is involved in Hippo, Wnt, p53, and SMAD signal transduction.…”