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Role of Hepatocyte Nuclear Factor 4 alpha in Promotion of Hepatocellular Carcinoma
Author(s) -
Walesky Chad,
Gunewardena Sumedha,
Edwards Genea,
Borude Prachi,
Apte Udayan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.387.11
Subject(s) - gene knockdown , hepatocyte nuclear factor 4 , hepatocyte , cancer research , hepatocyte nuclear factors , cyclin d1 , hepatocellular carcinoma , cell growth , biology , gene expression , gene , microbiology and biotechnology , cell cycle , transcription factor , genetics , nuclear receptor , in vitro
Recent studies indicate that HNF4α inhibits hepatocyte proliferation but the mechanisms are unclear. We investigated the mechanisms of HNF4α‐mediated inhibition of hepatocyte proliferation using an inducible HNF4α knockdown mouse model. Deletion of HNF4α in adult mice resulted in increased hepatocyte proliferation. RNA seq‐mediated global gene expression analysis revealed that a significant number of the 500+ up‐regulated genes are associated with cell proliferation and cancer. A combined bioinformatics analysis of ChIP‐seq/RNA‐seq data indicated that a substantial number of up‐regulated genes are putative HNF4α targets. IPA analysis revealed the most significantly activated gene network following HNF4α deletion is regulated by c‐Myc. To determine the role of HNF4α in the pathogenesis of HCC, we utilized the diethylnitrosamine (DEN)‐induced HCC model. Deletion of HNF4α resulted in promotion of DEN‐induced hepatic tumors, which were highly proliferative, less differentiated, and exhibited a significant up‐regulation of pro‐mitogenic proteins (c‐ Myc and Cyclin D1). These data indicate that HNF4α inhibits hepatocyte proliferation and is a tumor suppressor gene in the liver.