Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma

Abstract

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas.

A genome-wide interactome of DNA-associated proteins in the human liver

“…6A). HNF4A exhibited the strongest enrichment for binding near genes down-regulated in cancer, in agreement with previous observations implicating it as a tumor suppressor gene (Ning et al 2010;Bonzo et al 2012). GABPA and SP1 showed strong enrichment (FDR < 0.05) for binding near genes up-regulated in tumor tissue.…”

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

“…It has been shown that the majority of de-differentiated hepatoma cell lines and tissues fail to express HNF4a, but forced expression of this factor is sufficient to re-express a set of hepatocyte marker genes and restore the epithelial morphology of these cells (Späth and Weiss, 1998;Tanaka et al, 2006), which implies that it plays a role in the regulation of EMT. Moreover, forced expression of HNF4a completely induces the differentiation of hepatoma cells into hepatocytes in mice and blocks hepatocarcinogenesis in rats (Ning et al, 2010;Yin et al, 2008). However, the molecular mechanisms by which HNF4a maintains the differentiated liver epithelium and inhibits EMT have not been completely explored.…”

Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice

“…Thus, alterations in HNF4␣ functionality may increase the risk for development of HCC. Indeed, several mouse and human studies have shown that HNF4␣ expression is diminished in HCC (15)(16)(17)(18). Additionally, it was demonstrated that overexpression of HNF4␣ in rodent HCC models blocks carcinogenesis and metastasis, thus indicating a potential role for HNF4␣ as a tumor suppressor (16,19).…”