title: FXR induces SOCS3 and suppresses hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Lyu
authors.affiliation: Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099150:Receptor, Farnesoid X-Activated; C106644:SOCS3 protein, human; C412815:GW 4064
keywords: FXR; HCC; SOCS3; STAT3