Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma
Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma
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DOI：
10.1158/0008-5472.can-10-0824
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发表时间：
2010-10-01
期刊：
影响因子：
11.2
通讯作者：
Xie, Wei-Fen
中科院分区：
文献类型：
--
作者：
Ning, Bei-Fang;Ding, Jin;Xie, Wei-Fen
肝细胞核因子4 α（HNF 4 α）是一种转录因子，在肝细胞分化和维持肝功能中起关键作用，但其在肝癌发生中的作用尚未得到研究。在这里，我们报告HNF 4 α在肝癌中抑制作用的证据。在二乙基亚硝胺诱导的大鼠肝癌模型中，HNF 4 α表达进行性降低。在人肝组织中，HNF 4 α表达在肝硬化组织中降低，并且相对于健康组织在肝癌中进一步降低。值得注意的是，与上皮间质转化（EMT）存在负相关。HNF 4 α的高表达可减弱肝癌发生过程中的肝细胞EMT，减轻肝纤维化，阻断肝癌的发生。同时，干细胞标志物基因的表达沿着癌症干/祖细胞的产生而受到抑制。此外，HNF 4 α的强制表达抑制了β-连环蛋白的活化，这与EMT和肝癌发生密切相关。总之，我们的研究结果表明，HNF 4 α对HCC发展的抑制作用可能归因于通过抑制β-连环蛋白信号通路抑制肝细胞EMT和癌症干细胞的产生。更一般地说，我们的研究结果拓宽了对HNF 4 α在HCC发展中的生物学意义的认识，并且它们意味着通过操纵各种类型癌中的分化决定转录因子来预防HCC的新策略。Cancer Res; 70（19）; 7640-51. (C)2010年AACR。
Hepatocyte nuclear factor 4 alpha (HNF4 alpha) 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 HNF4 alpha in liver cancer. HNF4 alpha expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4 alpha 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 HNF4 alpha 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 HNF4 alpha inhibited activation of beta-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4 alpha on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of beta-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4 alpha in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas. Cancer Res; 70(19); 7640-51. (C) 2010 AACR.