Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma.
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.
Ning
Bei-Fang
BF
Department of Gastroenterology, Changzheng Hospital, Shanghai, China.
Ding
Jin
J
Yin
Chuan
C
Zhong
Wei
W
Wu
Kun
K
Zeng
Xin
X
Yang
Wen
W
Chen
Yue-Xiang
YX
Zhang
Jun-Ping
JP
Zhang
Xin
X
Wang
Hong-Yang
HY
Xie
Wei-Fen
WF
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051176:beta Catenin / Q000378:metabolism
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D051176:beta Catenin