Insights into the etiology-associated gene regulatory networks in hepatocellular carcinoma from The Cancer Genome Atlas.

BACKGROUND AND AIM: Hepatitis B virus (HBV), hepatitis C virus, alcohol consumption, and non-alcoholic fatty liver disease are the major known risk factors for hepatocellular carcinoma (HCC). There have been very few studies comparing the underlying biological mechanisms associated with the different etiologies of HCC. In this study, we hypothesized the existence of different regulatory networks associated with different liver disease etiologies involved in hepatocarcinogenesis.

METHODS: Using upstream regulatory analysis tool in ingenuity pathway analysis software, upstream regulators (URs) were predicted using differential expressed genes for HCC to facilitate the interrogation of global gene regulation.

RESULTS: Analysis of regulatory networks for HBV HCC revealed E2F1 as activated UR, regulating genes involved in cell cycle and DNA replication, and HNF4A and HNF1A as inhibited UR. In hepatitis C virus HCC, interferon-γ, involved in cellular movement and signaling, was activated, while IL1RN, mitogen-activated protein kinase 1 involved in interleukin 22 signaling and immune response, was inhibited. In alcohol consumption HCC, ERBB2 involved in inflammatory response and cellular movement was activated, whereas HNF4A and NUPR1 were inhibited. For HCC derived from non-alcoholic fatty liver disease, miR-1249-5p was activated, and NUPR1 involved in cell cycle and apoptosis was inhibited. The prognostic value of representative genes identified in the regulatory networks for HBV HCC can be further validated by an independent HBV HCC dataset established in our laboratory with survival data.

CONCLUSIONS: Our study identified functionally distinct candidate URs for HCC developed from different etiologic risk factors. Further functional validation studies of these regulatory networks could facilitate the management of HCC towards personalized medicine.