Hepatocyte nuclear factor 4 alpha deletion promotes... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents

Walesky, Chad1; Edwards, Genea1; Borude, Prachi1; Gunewardena, Sumedha2,3; O'Neil, Maura4; Yoo, Byunggil5; Apte, Udayan1,*

1_Department of Pharmacology, Toxicology and Therapeutics_

2_Department of Molecular and Integrative Physiology_

3_Department of Biostatistics_

4_Department of Pathology_

5_Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS_

*Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., MS1018, Kansas City, KS 66160

Email:[email protected]

Received 19 June 2012; Accepted 13 December 2012

View this article online atwileyonlinelibrary.com.

Grant sponsor: NIH; Grant Number: P20 RR021940; Grant sponsor: AASLD/ALF Liver Scholar Award; Grant sponsor: Kansas University Medical Center-Microarray Facility (KUMC-MF); Grant sponsor: Kansas University-School of Medicine; Grant sponsor: KUMC Biotechnology Support Facility; Grant sponsor: Smith Intellectual and Developmental Disabilities Research Center; Grant Number: HD02528; Grant sponsor: Kansas IDeA Network of Biomedical Research Excellence; Grant Number: RR016475.

Potential conflict of interest: Nothing to report.

Abstract

Hepatocyte nuclear factor 4 alpha (HNF4α), the master regulator of hepatocyte differentiation, has been recently shown to inhibit hepatocyte proliferation by way of unknown mechanisms. We investigated the mechanisms of HNF4α-induced inhibition of hepatocyte proliferation using a novel tamoxifen (TAM)-inducible, hepatocyte-specific HNF4α knockdown mouse model. Hepatocyte-specific deletion of HNF4α in adult mice resulted in increased hepatocyte proliferation, with a significant increase in liver-to-body-weight ratio. We determined global gene expression changes using Illumina HiSeq-based RNA sequencing, which revealed that a significant number of up-regulated genes following deletion of HNF4α were associated with cancer pathogenesis, cell cycle control, and cell proliferation. The pathway analysis further revealed that c-Myc-regulated gene expression network was highly activated following HNF4α deletion. To determine whether deletion of HNF4α affects cancer pathogenesis, HNF4α knockdown was induced in mice treated with the known hepatic carcinogen diethylnitrosamine (DEN). Deletion of HNF4α significantly increased the number and size of DEN-induced hepatic tumors. Pathological analysis revealed that tumors in HNF4α-deleted mice were well-differentiated hepatocellular carcinoma (HCC) and mixed HCC-cholangiocarcinoma. Analysis of tumors and surrounding normal liver tissue in DEN-treated HNF4α knockout mice showed significant induction in c-Myc expression. Taken together, deletion of HNF4α in adult hepatocytes results in increased hepatocyte proliferation and promotion of DEN-induced hepatic tumors secondary to aberrant c-Myc activation.