atocyte Nuclear Factor 4 α Suppresses the Development R epatocellular Carcinoma

Downloa atocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte ntiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to mined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression rogressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human issues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma e to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition . Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated c fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene sion was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. together, our results suggest that the inhibitory effect of HNF4α on HCC development might be ted to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of nin signaling pathways. More generally, our findings broaden knowledge on the biological significance F4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of HN of differentiation-determining transcription factors in various types of carcinomas. Cancer Res; 70(19); 7640–51. ©2010 AACR.