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

Abstract

HNF4α, the master regulator of hepatocyte differentiation, has been recently shown to inhibit hepatocyte proliferation via unknown mechanisms. We investigated the mechanisms of HNF4α-induced inhibition of hepatocyte proliferation using a novel 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.

Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

“…Previous studies involving inducible HNF4a deletion support of our findings (Bonzo et al, 2012;Walesky et al, 2013). When re-analyzing the microarray and RNA sequencing data we found that hepatocyte-specific deletion of HNF4a in adult mice resulted in upregulation of many Wnt target genes including Myc, Ccnd1 (cyclin D1), Vegf, Sox9, Egfr and Jun.…”

Splicing regulator SLU7 is essential for maintaining liver homeostasis

“…Hepatocyte-specific deletion of Hnf4α results in hepatocellular dedifferentiation and proliferation and promotes chemically induced hepatocarcinogenesis. These responses were accompanied by upregulation of the promitogenic genes Egr1, Myc, and Ccnd1 (17,(56)(57)(58), which were also detected in Slu7-depleted mice. Interestingly, CCND1 can also interfere with HNF4α transcriptional activity (57), while increased c-Myc levels modulate the switch in GLS1 and GLS2 expression (38) and, through the induction of hnRNPA1, can promote the expression of HK2 and PKM2 favoring glycolytic metabolism (38, 59).…”

Advances in cholangiocarcinoma research: report from the third Cholangiocarcinoma Foundation Annual Conference

“…Specifically, he is focusing on potential interactions between the Wnt/β-catenin pathway and hepatocyte nuclear factor 4 alpha (HNF4α), molecules that are involved in the development of the liver as well as CCA (35)(36)(37)(38)(39)(40). Studies in the laboratory have shown that knockdown of HNF4α in the zebrafish leads to a reduction in hepatocyte differentiation while genetic or chemical increase in β-catenin results in a loss of HNF4α and a maintenance of cholangiocyte differentiation.…”