G蛋白偶联受体Gpbar1(TGR5)在胃癌中的作用和分子机制研究

Elucidating the mechanisms of gastric carcinogenesis could lead to life-saving therapy for a large number of patients with gastric cancer. Most recently, our publications show that bile acid membrane receptor Gpbar1 (G-protein-coupled bile acid receptor, TGR5) negatively regulates gastric inflammatory response through antagonizing NF-κB signaling pathway, which indicates that TGR5 is a key negative regulator in chronic inflammation. We also found that TGR5 activation is able to suppress SGC7901 gastric cancer cell proliferation and migration. TGR5 activation significantly inhibits signal transducer and activator of transcription 3 (STAT3) activity in gastric cancer cells through suppressing the phosphorylation of STAT3 and its transcription activity induced by lipopolysaccharide (LPS) or interleukin-6. Furthermore, our preliminary data show that TGR5 knockout mice are more sensitive to diethylnitrosamine (DEN)-induced gastric damage compared with wild-type mice. These results indicate that TGR5 plays a critical role in gastric tumour development as a negative regulator of gastric carcinogenesis. Sustained STAT3 activity is often found in gastric tumor, and inhibition of SATAT3 leads to antitumor activity in gastric carcinogenesis. Therefore, to better understand the molecular mechanisms by which TGR5 suppresses gastric cancer, we will focus on the potential relationship between TGR5 and STAT3 signaling pathway in this proposal. In Specific Aim 1 of this proposal, we will determine whether TGR5 antagonizes STAT3 signaling pathway in gastric cancer by regulating the interaction of β-arrestin1-JAK1-STAT3. In Specific Aim 2, we propose to identify the levels of TGR5 expression and endogenous TGR5 ligands such as bile acids at different stages of gastric cancer. In this specific aim, we will reveal the molecular mechanisms by which TGR5 expression is decreased during gastric tumour development. These results from this proposal will help us determine whether TGR5 is a potential therapeutic candidate for prevention and treatment of gastric cancer, which may also have potential implications for treatment of many other types of cancer.

揭示胃癌发病的机制有助于新药研发，挽救胃癌患者的生命。我们最近发表的工作表明，G蛋白偶联受体Gpbar1（TGR5）能够通过抑制NF-κB通路抑制炎症，是胃炎的关键抑制子。我们还发现激活TGR5可以抑制SGC7901胃癌细胞的活性和STAT3信号通路。预实验中，我们发现TGR5基因敲除小鼠对于DEN诱导的胃组织损伤非常敏感。这些结果表明TGR5在胃癌中起关键作用，可能是胃癌的负调控子。本课题中我们将鉴定TGR5拮抗STAT3信号通路和胃癌细胞活性的分子机制。此外，我们还将考察胃癌癌变过程中TGR5表达调控失衡的内在原因，鉴定胃正常组织中TGR5表达高和胃癌病变组织中TGR5表达低的转化分子机制。该项目内容均属首次阐述，所得结果有助于明确TGR5是否是开发潜在胃癌治疗药物的靶向因子，并对治疗其它类型的癌症具有借鉴意义。

揭示胃癌发病的机制有助于新药研发，挽救胃癌患者的生命。我们已发表的工作表明，G蛋白偶联受体Gpbar1（TGR5）能够通过抑制NF-κB通路抑制炎症，是胃炎的关键抑制子。我们发现激活TGR5可以抑制SGC7901胃癌细胞的增殖、迁移，并诱导细胞凋亡；同时TGR5激活可以抑制STAT3信号通路。在本项目中，我们揭示了TGR5基因敲除小鼠对于DEN诱导的胃组织损伤非常敏感，TGR5激活后能够抑制裸鼠中MGC-803细胞诱导的胃癌肿瘤。这些结果表明TGR5在胃癌中起关键作用，是胃癌的负调控子。本课题中我们也鉴定了TGR5拮抗STAT3信号通路和胃癌细胞活性的分子机制。我们发现TGR5可以抑制STAT3磷酸化，可能的路径是TGR5调控β-arrestin1的表达，但不依赖于cAMP路径。TGR5可通过调控β-arrestin1，进而降低β-arrestin1与JAK1和STAT3间的相互作用，拮抗STAT3信号通路，抑制胃癌细胞的增殖和胃癌的发生。此外，我们还考察了胃癌癌变过程中TGR5表达调控失衡的内在原因，鉴定了胃正常组织中TGR5表达高和胃癌病变组织中TGR5表达低的转化分子机制。该项目所得结果能够从一个崭新的视角阐明胃癌的发病机制，并且能够在分子水平提供TGR5作为预防和治疗胃癌药物靶向的理论基础，有助于推动以TGR5为靶向因子的新药开发。所得结果也可能对治疗其它器官癌症具有借鉴意义。