Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis

Authors

  • Wei-Dong Chen,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH
    2. Key laboratory of receptors-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, P. R. China
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  • Donna Yu,

    1. Department of Gene Regulation and Drug Discovery, BeckmanResearch Institute, City of Hope National Medical Center, Duarte, CA
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  • Barry M. Forman,

    1. Department of Gene Regulation and Drug Discovery, BeckmanResearch Institute, City of Hope National Medical Center, Duarte, CA
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  • Wendong Huang,

    Corresponding author
    1. Department of Gene Regulation and Drug Discovery, BeckmanResearch Institute, City of Hope National Medical Center, Duarte, CA
    • Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010
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  • Yan-Dong Wang

    Corresponding author
    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH
    2. Key laboratory of receptors-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, P. R. China
    3. Department of Gene Regulation and Drug Discovery, BeckmanResearch Institute, City of Hope National Medical Center, Duarte, CA
    • Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272
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    • fax: 330-325-5910


  • Potential conflict of interest: Nothing to report.

  • Supported by the National Natural Science Foundation of China (Grant No. 81270522) to W.-D. C., NCI R01-139158 to W.H.; the City of Hope GI Cancer Program GI Cancer Research Pilot Fund to Y.-D.W.

Abstract

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 activation also inhibits nuclear factor κB (NF-κB)-mediated inflammation. Here we show that TGR5 deficiency enhances chemically induced liver carcinogenesis, and that TGR5 is a negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling. Mice lacking TGR5 were much more susceptible to diethylnitrosamine (DEN)-induced acute liver injury and liver carcinogenesis than wildtype (WT) mice. Consistent with the increasing incidence of liver cancer in TGR5−/− mice, hepatocyte death, compensatory proliferation, and gene expression of certain inflammatory cytokines and matrix metalloproteinases were more sensitive to DEN induction in the absence of TGR5 signaling. In vitro, TGR5 activation greatly inhibited proliferation and migration of human liver cancer cells. We then found that TGR5 activation strongly suppressed STAT3 signaling in vitro and in vivo. Furthermore, we observed that TGR5 antagonizes the STAT3 pathway through suppressing STAT3 phosphorylation, its transcription activity, and DNA binding activity, which suggests that TGR5 antagonizes liver tumorigenesis at least in part by inhibiting STAT3 signaling. Conclusion: These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer. (HEPATOLOGY 2013;)

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