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

PLoS One. 2017 Mar 29;12(3):e0174142. doi: 10.1371/journal.pone.0174142. eCollection 2017.

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.

MeSH terms

  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Computational Biology
  • Databases, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / immunology*
  • Gene Regulatory Networks / immunology*
  • Humans
  • Immunity, Innate
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / etiology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • Transcription Factors / genetics*
  • Transcription Factors / immunology

Substances

  • MicroRNAs
  • RNA, Long Noncoding
  • RNA, Messenger
  • Transcription Factors

Grants and funding

This study was supported by the National Natural Science Foundation of China (grant no. 81370566; grant no. 81170397; grant no. 81570579; grant no. 81570581) and Harbin Medical University Postgraduate Innovative Research Projects (grant no. YJSCX2015-19HYD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.