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 BF ，Ding J ，Yin C ，Zhong W ，Wu K ，Zeng X ，Yang W ，Chen YX ，Zhang JP ，Zhang X ，Wang HY ，Xie WF ... -  《-》

Gankyrin-mediated dedifferentiation facilitates the tumorigenicity of rat hepatocytes and hepatoma cells.

Gankyrin is a critical oncoprotein overexpressed in human hepatocellular carcinoma (HCC). However, the mechanism underlying gankyrin-mediated hepatocarcinogenesis remains elusive. Herein, we provide evidence that gankyrin expression was progressively elevated in liver fibrosis, cirrhosis, and HCC. Levels of gankyrin expression were closely associated with the dedifferentiation status of hepatoma in patients. Decrease of hepatocyte characteristic markers and increase of cholangiocyte-specific markers were observed in rat primary hepatocytes with enforced gankyrin expression and diethylnitrosamine (DEN)-triggered rat hepatocarcinogenesis. Overexpression of gankyrin also attenuated the hepatic function of primary hepatocytes, which further suggests that gankyrin promotes the dedifferentiation of hepatocytes. Moreover, elevated expression of gankyrin closely correlated with the expression of HCC stem/progenitor cell markers in DEN-triggered hepatocarcinogenesis and human HCCs. Hepatoma cells derived from suspension-cultured spheroids exhibited a higher gankyrin level, and enforced gankyrin expression in hepatoma cells remarkably enhanced cluster of differentiation (CD)133, CD90, and epithelial cellular adhesion molecule expression, indicating a role of gankyrin in hepatoma cell dedifferentiation and the generation of hepatoma stem/progenitor cells. In contrast, down-regulation of gankyrin in hepatoma cells by lentivirus-mediated microRNA delivery significantly improved their differentiation status and attenuated malignancy. Interference of gankyrin expression in hepatoma cells also diminished the proportion of cancer stem/progenitor cells and their self-renewal capacity. Furthermore, gankyrin was found to bind hepatocyte nuclear factor 4α (HNF4α), which determines hepatocyte differentiation status and enhances proteasome-dependent HNF4α degradation in hepatoma cells. The inverse correlation of gankyrin and HNF4α was further confirmed in primary hepatocytes, DEN-induced hepatocarcinogenesis, and human HCCs. Gankyrin-mediated dedifferentiation of hepatocytes and hepatoma cells via, at least partially, down-regulation of HNF4α facilitates HCC development, and interference of gankyrin expression could be a novel strategy for HCC prevention and differentiation therapy.

Sun W ，Ding J ，Wu K ，Ning BF ，Wen W ，Sun HY ，Han T ，Huang L ，Dong LW ，Yang W ，Deng X ，Li Z ，Wu MC ，Feng GS ，Xie WF ，Wang HY ... -  《-》

A double-negative feedback loop between Wnt-β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma.

Yang M ，Li SN ，Anjum KM ，Gui LX ，Zhu SS ，Liu J ，Chen JK ，Liu QF ，Ye GD ，Wang WJ ，Wu JF ，Cai WY ，Sun GB ，Liu YJ ，Liu RF ，Zhang ZM ，Li BA ... -  《-》

Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats.

Yue HY ，Yin C ，Hou JL ，Zeng X ，Chen YX ，Zhong W ，Hu PF ，Deng X ，Tan YX ，Zhang JP ，Ning BF ，Shi J ，Zhang X ，Wang HY ，Lin Y ，Xie WF ... -  《-》

Tg737 regulates epithelial-mesenchymal transition and cancer stem cell properties via a negative feedback circuit between Snail and HNF4α during liver stem cell malignant transformation.

Determining the origin of liver cancer stem cells is important for treating hepatocellular carcinoma. Tg737 deficiency plays an important role in the malignant transformation of liver stem cells, but the underlying mechanism remains unclear. Here we established a chemical-induced mouse hepatoma model and found that Tg737 and hepatocyte nuclear factor 4-alpha (HNF4α) expression decreased and epithelial-mesenchymal transition (EMT)-related marker expression increased during liver cancer development. To investigate the underlying mechanism, we knocked down Tg737 in WB-F344 (WB) rat hepatic oval cells. Loss of Tg737 resulted in nuclear β-catenin accumulation and activation of the Wnt/β-catenin pathway, which further promoted EMT and the malignant phenotype. XAV939, a β-catenin inhibitor, attenuated WB cell malignant transformation due to Tg737 knockdown. To clarify the relationships of Tg737, the β-catenin pathway, and HNF4α, we inhibited Snail and overexpressed HNF4α after Tg737 knockdown in WB cells and found that Snail and HNF4α comprise a negative feedback circuit. Taken together, the results showed that Tg737 regulates a Wnt/β-catenin/Snail-HNF4α negative feedback circuit, thereby blocking EMT and the malignant transformation of liver stem cells to liver cancer stem cells.

Huang Q ，Pu M ，Zhao G ，Dai B ，Bian Z ，Tang H ，Chen C ，Liu W ，Qu X ，Shen L ，Tao K ... -  《-》