Research Article: Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis

Date Published: March 29, 2017

Publisher: Public Library of Science

Author(s): Bo Gao, Xueming Zhang, Yongming Huang, Zhengpeng Yang, Yuguo Zhang, Weihui Zhang, Zu-hua Gao, Dongbo Xue, Partha Mukhopadhyay.


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.

Partial Text

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]. Histologically, immune-mediated liver damage presents as a loss of hepatocytes and the accumulation of lymphocytes, macrophages, and stromal cells, which interact in a paracrine manner through the secretion of proteins including chemokines and cytokines. Therefore, elucidating the gene regulatory network for the immunological processes that lead to liver cirrhosis could help to characterize its pathogenesis to develop more effective therapies.

Clinically and pathologically, liver cirrhosis is a consequence of immune-mediated hepatocyte damage and repair processes. We used 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. Our results confirm that liver cirrhosis and the immune response are closely associated. To further understand the pathogenesis of liver cirrhosis, we unveiled the regulatory coding and non-coding genes for the immunological processes that eventually lead to the development of liver cirrhosis.




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