Abstract
Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including “immune response” as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma.
Highlights
Liver cirrhosis is a common end point for various chronic liver diseases including chronic viral hepatitis due to hepatitis B or hepatitis C viral infections, alcoholic or nonalcoholic fatty liver disease, autoimmune hepatitis, biliary disorders and inherited metabolic defects[1]
Based on the dataset GSE63046, we identified 46 differentially expressed (DE) miRNAs, including 6 upregulated and 40 downregulated miRNAs in liver cirrhosis. (S1 Table) we built a heatmap of these DE mRNAs, miRNAs and long non-coding RNAs (lncRNAs) (Fig 1A)
We used gene ontology (GO) analysis of DE mRNAs in liver cirrhosis samples and found a large number of significantly different GO terms related to the immune response as compared to control samples
Summary
Liver cirrhosis is a common end point for various chronic liver diseases including chronic viral hepatitis due to hepatitis B or hepatitis C viral infections, alcoholic or nonalcoholic fatty liver disease, autoimmune hepatitis, biliary disorders and inherited metabolic defects[1]. Regardless of specific etiology, immune-mediated liver damage in each of these diseases eventually leads to liver cirrhosis[2]. Immune response network in liver cirrhosis collection and analysis, decision to publish, or preparation of the manuscript
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