Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma
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Xijun Liu1, Xingwang Zhang1, Lingling Ji1, Jianxin Gu1, Meiling Zhou2, She Chen1
1Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical college, Fudan University, Shanghai, China
2Department of Radiology, Zhongshan Hospital of Fudan University, and Shanghai Institute of Medical Imaging, Shanghai, China
She Chen, e-mail: [email protected]
Meiling Zhou, e-mail: [email protected]
Keywords: Farnesoid X receptor, β-Catenin, TCF4, Hepatocellular carcinoma
Received: August 29, 2014 Accepted: December 15, 2014 Published: December 29, 2014
The association between the temporal activation of Wnt/β-catenin pathway and the spontaneous hepatocellular carcinoma (HCC) development in Farnesoid X receptor (FXR) knockout mice is not well understood. We found that Huh7 cells depleted with FXR by RNAi showed enhanced cell growth, migration and invasion in vitro and accelerated tumor xenografts formation in nude mice. And these phenotypes were attenuated by simultaneous knockdown of β-catenin with RNAi. Furthermore, we identified that FXR could bind with β-Catenin through AF1 domain, and disrupt the assembly of the core β-Catenin/TCF4 complex. Activation of FXR attenuated the DNA-binding activity of β-Catenin/TCF4, and subsequently, its targeting gene-cyclin D1 expression. Importantly, FXR expression was markedly reduced in human HCC, an event which correlated with aberrant activation of β-Catenin. These data identified FXR as a negative regulator of HCC development through direct suppression of Wnt/β-catenin pathway.
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