Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
Hepatology. 2013 Feb;57(2):656-66. doi: 10.1002/hep.26019.
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.
These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.
Gpbar1（TGR5）是一种膜结合胆汁酸受体，其在调节能量平衡和葡萄糖代谢方面的作用众所周知。TGR5 激活还能抑制核因子 κB（NF-κB）介导的炎症。在这里，我们表明 TGR5 缺乏会增强化学诱导的肝癌发生，并且 TGR5 是信号转导和转录激活因子 3（STAT3）信号的负调节剂。缺乏 TGR5 的小鼠比野生型（WT）小鼠更容易受到二乙基亚硝胺（DEN）诱导的急性肝损伤和肝癌发生。与 TGR5（-/-）小鼠肝癌发生率增加一致，在没有 TGR5 信号的情况下，肝细胞死亡、代偿性增殖以及某些炎症细胞因子和基质金属蛋白酶的基因表达对 DEN 诱导更为敏感。在体外，TGR5 激活可大大抑制人肝癌细胞的增殖和迁移。然后，我们发现 TGR5 激活在体外和体内均能强烈抑制 STAT3 信号。此外，我们观察到 TGR5 通过抑制 STAT3 磷酸化、转录活性和 DNA 结合活性来拮抗 STAT3 途径，这表明 TGR5 通过抑制 STAT3 信号至少部分拮抗肝肿瘤发生。
这些发现确定了 TGR5 是一种新型的肝脏肿瘤抑制因子，它可能成为人类肝癌有吸引力的治疗工具。
