FXR induces SOCS3 and suppresses hepatocellular carcinoma
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Fei Guo1,*, Zhizhen Xu2,*, Yan Zhang2, Peng Jiang1, Gang Huang2, Shan Chen2, Xilin Lyu2, Ping Zheng1, Xin Zhao1, Yijun Zeng2, Shuguang Wang1, Fengtian He2
1Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
2Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
*These authors have contributed equally to this work
Fengtian He, e-mail: [email protected]
Shuguang Wang, e-mail: [email protected]
Keywords: HCC, FXR, SOCS3, STAT3
Received: April 23, 2015 Accepted: September 11, 2015 Published: September 21, 2015
Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC.
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