多药耐药是导致胃癌化疗失败，患者死亡的重要因素，其机制尚未完全阐明。糖基化是最重要的蛋白翻译后修饰之一，与多种肿瘤的耐药表型密切相关，但目前尚无与胃癌多药耐药的研究。本项目前期研究发现胃癌多药耐药细胞中蛋白总体糖基化水平升高，而能够促进糖基化的糖基转移酶UGT1在耐药细胞中表达明显升高，且高表达UGT1的细胞中P-gp糖基化水平明显升高，提示UGT1可能通过促进P-gp的糖基化，参与调节胃癌的耐药表型。本项目拟在前期基础上，进一步研究UGT1对胃癌细胞耐药性的影响；通过各种体内、外实验探讨UGT1通过上调P-gp糖基化，促进胃癌耐药的机制；最后通过胃癌组织标本明确UGT1、总P-gp及糖基化P-gp的临床意义。本项目将有助于深入诠释UGT1参与调节肿瘤多药耐药的分子机理，明确蛋白糖基化在胃癌多药耐药过程中的作用，并最终对于阐明胃癌多药耐药的产生机制具有重要指导意义。

Gastric cancer is the second leading cause of cancer mortality worldwide. The major cause of treatment failure for gastric cancer is the development of multidrug resistance (MDR) to chemotherapy, which is one of the primary treatment options.But the underlying mechanisms of MDR are still not clear. Glycosylation is considered as one of the most important and common protein post-translational modifications and is associated with drug resistance in many tumors. But currently, there is no report about the relation between glycosylation and MDR in gastric cancer. Previously we performed MDR related glycoproteomics research in gastric cancer and found that the total glycosylation level in MDR cell lines are increased compared with that in parental gastric cancer cell. Then we examined several common glycosylases and found UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1), which could promote glycosylation, was dramatically increased in gastric cancer MDR cells. Subsequently, we found that the glycosylation level of P-glycoprotein was significantly higher in UGT1 up-regulated cells than that in control cells. Therefore, it suggested that UGT1 may promote the development of MDR in gastric cancer by up-regulating glycosylation on P-gp protein.In this subject, firstly we are planning to investigate the role of UGT1 in MDR of gastric cancer. Then the mechanisms by which glycosylated P-gp would mediate the promotional effect of UGT1 on MDR in gastric cancer. Finally, the clinical value of UGT1, total P-gp and glycoaylated P-gp in gastric cancer will be determined. This work would be not only helpful to clarify the function of UGT1 in MDR of gastric cancer, but also be helpful to better understand the significance of glycosylation in cancers and the developent of MDR in gastric cancer, and valuable for prevention and turnover of MDR in gastric cancer.