去氧胆酸调控的IL-6-JAK-STAT3信号通路对胃癌发生发展的作用机制

Gastric cancer is one of malignant tumor which has serious threat to human health in the worldwide. Duodenal bile acid refluxing plays an important role in the progression of gastric cancer according to the clinical reports. However, little is known about whether there exists a direct correlation between refluxed bile acid and gastric cancer, as well as its mechanisms up to now. In our previous research, we found that a number of bile acids were significantly high in the gastric tissues and juices of the gastritis with bile acid reflxuing, among which the cytotoxic deoxycholic acids (DCA) was dramatically higher compared with those without gastric cancer or no refluxed bile acid. Meanwhile, we found that upregulated DCA could induce increased expression of IL-6. IL-6 is an important factor which mediates JAK-STAT3 signaling pathway, ultimately inducing onset of inflammatory and various cancers. Here, we hypothesize that DCA in bile acid refluxing may induce the onset and development of gastric cancer by mediating JAK-STAT3 signaling pathway thorough inflammatory factor IL-6. In this project, we will investigate how DCA impacts the inflammatory factor IL-6, as well as the JAK-STAT3 signaling pathway, aiming to elucidate the mechanism of DCA on the onset and progression of gastric cancer.

胃癌是危害人类生命健康的恶性肿瘤。临床研究显示，十二指肠反流胆汁酸是诱导胃癌发生的重要因素。但胆汁酸是否与胃癌的发生有直接关系，其作用机制又如何，目前尚未有明确的报道。申请人基于长期对癌症代谢研究的工作基础，在前期工作中发现，胃癌组织和胆汁酸反流胃炎胃液中的多种胆汁酸浓度显著升高，特别是具有细胞毒性的胆酸——去氧胆酸（DCA，deoxycholic acid）升高最为明显。同时，DCA的升高引起炎性细胞因子白介素-6（IL-6）亦升高，两者呈现显著的正相关。IL-6是介导JAK-STAT3经典信号通路激活，最终引发炎性和癌症发生的关键因素之一。因此，本项目提出反流胆汁酸DCA通过IL-6，激活JAK-STAT3信号通路，诱导胃癌发生发展的科学假说。项目研究将围绕DCA对炎性细胞因子IL-6的影响，对JAK- STAT3的调控作用，阐释胆汁酸DCA在胃癌发生中的作用机制。

胆汁酸反流胃炎与胃癌的发生有密切关系，但具体的作用机制仍不清楚。本项目首先系统研究了胃胆汁酸的定量方法，并比较了有胆汁反流胃炎和没有胆汁反流胃炎胃液中胆汁酸谱的特征。围绕反流胆汁酸、胃微生物组成变化在胃癌发生中的作用进行研究。研究结果显示，结合型胆汁酸、IL-6、脂多糖LPS以及能产生LPS的菌在胆汁反流胃炎和胃癌患者中显著升高，且次级胆汁酸甘氨去氧胆酸（TDCA）与产LPS的菌具有明显的正相关性。细胞实验研究结果显示，TDCA通过激活IL6-JAK1-STAT3信号通路促进正常的胃表皮细胞GES-1的增殖。这一结论进一步在两种动物模型，一种是正常小鼠上分别灌胃TDCA、LPS以及具有产LPS的菌Prevotella melaninogenica考察对胃炎胃癌发生的影响，另一种是采用模拟临床胆汁反流（进行肠胃吻合手术）的模型小鼠得到了验证。并且研究结果显示胆汁反流所致的胃癌前病变可以被STAT3的抑制剂隐丹参酮所抑制。该项目研究结果揭示了胆汁反流对胃癌形成的分子作用机制，并提供了一种具有潜在治疗效果的预防策略。. 在本项目的资助下，已发表论文11篇，其中SCI 8篇，包括在Cell Metabolism, Nature Communications高影响力的期刊上发表。研究内容还有1篇在投Advanced Science修改过程中，培养博士生1名。.