GnT-V/β1,6介导的E-钙粘蛋白异常糖基化在胃癌转移中的机制及消痰散结方对其调节作用的研究

Metastasis is the key factor which can influence the gastric carcinoma prognosis. In the previous study, we found that the abnormal pathway of GnT-V/β1,6 induced the increasing of N-glycan beta 1,6 branches is the characteristic phenomenon of abnormal glycosylation, which changes the adhesion and metastasis of the gastric carcinoma cells, and which enhances the metastasis. The pro-metastasis phenomenon, which was effected by the increasing of the N-glycan beta 1,6 branches, is quietly similar to the characteristic of the phlegm of traditional Chinese medicine theory. Based on this theory, we created the Xiao tan San jie decoction, which inhibited the expression of the glycan chain and prevented the gastric carcinoma metastasis. But the pro-metastasis mechanism remains unknown. It was reported that the adhesion of the E-cadherin was changed with increasing of the beta 1,6 branches of N-glycan, we also found this phenomenon in the pre-experiment of gastric cancer cell. We hypothesis that the functional changes of the E-cadherin, which is effected by the branches increasing, is an important mechanism for gastric carcinoma metastasis. We will investigate the regulation of the increasing branches on the function of the E-cadherin and the metastasis of the gastric carcinoma, both in vitro and in vivo. Through the regulation of Xiao tan San jie decoction on the beta 1,6 branches to E-cadherin pathway, the mechanism of regulation on the abnormal glycosylation of preventing gastric metastasis based on phlegm will be discussed.

侵袭转移是影响胃癌预后的关键因素。课题组前期研究发现，GnT-V/β1,6通路异常导致的N糖β1,6分支增多是胃癌糖基化异常的特征性表现，这一异常导致胃癌细胞粘附、迁徙能力的增强，从而促进了胃癌转移。这与中医“痰”性粘滞、攻窜流走特点极为相似，基于此研制的消痰散结方能通过降低该糖链的含量而预防胃癌转移。但是，β1,6分支增多后促进胃癌转移的机制尚不明确。文献学习发现，β1,6分支的增多可引起E-Cad黏附功能减弱从而促进细胞迁徙，预实验发现胃癌细胞也存在这一现象。我们推测，β1,6分支增多导致E-Cad功能的改变可能是糖基化异常促进胃癌转移的重要机制。课题组拟通过体内和体外实验，揭示β1,6分支对胃癌细胞中E-Cad功能的调控机制及其在胃癌转移中的作用；通过药物干预，观察消痰散结方对β1,6/E-Cad途径的调节作用，阐明消痰散结通过调节异常糖基化预防胃癌转移的机制。

胃癌是全球常见的恶性肿瘤，预后相对较差，侵袭转移是影响其预后的关键因素。课题组前期研究发现，GnT-V/β1,6通路异常导致的N糖β1,6分支增多是胃癌糖基化异常的特征性表现，这一异常导致胃癌细胞粘附、迁徙能力的增强，从而促进了胃癌转移。这与中医“痰”性粘滞、攻窜流走特点极为相似，基于此研制的消痰散结方能通过降低该糖链的含量而预防胃癌转移。但是，β1,6分支增多后促进胃癌转移的机制尚不明确。文献学习发现，β1,6分支的增多可引起E-Cad黏附功能减弱从而促进细胞迁徙，预实验发现胃癌细胞也存在这一现象。我们推测，β1,6分支增多导致E-Cad功能的改变可能是糖基化异常促进胃癌转移的重要机制。本研究内容两部分：①筛选N糖1,6分支高表达和低表达胃癌细胞株，通过质粒转染促进或抑制N糖1,6分支的表达，观察1,6分支对E-cad黏附的影响；②借助体内和体外实验，检测1,6/E-cad通路对胃癌侵袭转移的影响；通过消痰散结方干预，通过体内和体外实验观察消痰散结方对1,6/E-cad途径的调节作用，阐明其预防胃癌转移的机制。课题组通过体内和体外实验，揭示β1,6分支对胃癌细胞中E-Cad功能的调控机制及其在胃癌转移中的作用；通过药物干预，观察消痰散结方对β1,6/E-Cad途径的调节作用，成功证实消痰散结通过调节异常糖基化预防胃癌转移的机制。