Article first published online: 5 FEB 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 656–666, February 2013
How to Cite
Chen, W.-D., Yu, D., Forman, B. M., Huang, W. and Wang, Y.-D. (2013), Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis. Hepatology, 57: 656–666. doi: 10.1002/hep.26019
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.
- Issue published online: 5 FEB 2013
- Article first published online: 5 FEB 2013
- Accepted manuscript online: 22 AUG 2012 03:21AM EST
- Manuscript Accepted: 7 AUG 2012
- Manuscript Received: 27 APR 2012
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;)