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


CONCLUSIONS
These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
Wei-Dong
WD
Chen
Donna
D
Yu
Barry M
BM
Forman
Wendong
W
Huang
Yan-Dong
YD
Wang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine; D006801:Humans; D017114:Liver Failure, Acute / Q000139:chemically induced; D008113:Liver Neoplasms / Q000139:chemically induced*; D051379:Mice; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency*; D050796:STAT3 Transcription Factor / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D025521:Tumor Suppressor Proteins; D004052:Diethylnitrosamine