p53突变抑制CXCR2诱导的细胞衰老在H. pylori感染相关性胃癌发生中的作用及机制

项目名称： p53突变抑制CXCR2诱导的细胞衰老在H. pylori感染相关性胃癌发生中的作用及机制

项目编号： No.81472260

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐建波

作者单位： 中山大学

项目金额： 65万元

中文摘要： 慢性炎症是幽门螺杆菌（H. pylori）致癌的重要原因，但机制未明。我们前期研究表明H. pylori感染是胃癌独立的预后不良因素，发现H. pylori可以激活TLR4/NF-κB途径释放趋化因子IL-8/CXCL1；并证实了CXCL1/CXCR2轴可以促进胃癌进展。既往报道CXCR2通过依赖p53的机制诱导细胞衰老抑制肿瘤生长；而H. pylori感染常导致p53突变。由此，我们提出H. pylori感染导致恶性转化的新机制：p53突变通过抑制CXCR2介导的细胞衰老促进胃癌的发生。本项目拟首先观察H. pylori在胃癌及癌前病变的感染状态及其与p53蛋白的关系；继而通过细胞实验证实p53突变是胃粘膜细胞从衰老到癌变表型转换的关键；最后明确p53突变对CXCR2表达的调控机制。本项目旨在阐明H. pylori感染导致的慢性炎症与胃粘膜癌变的关系，从而为胃癌的早期防治提供新的策略。

中文关键词： C07_胃肿瘤；p53突变；细胞衰老；幽门螺杆菌；肿瘤发生

英文摘要： Chronic inflammation induced by H. pylori infection is proved an important carcinogenic factor for gastric cancer， while the mechanism remains to be elucidated. We have demonstrated that H. pylori infection is an independent predictive factor of poor prognosis for gastric cancer. Our previous studies also showed that H. pylori activated TLR4/NF-κB pathway and promoted the release of chemokines IL-8 and CXCL1. We also found that CXCL1/CXCR2 axis can promote cancer progression. However, it has been reported that CXCR2 had an anti-tumor effect by activating the senescence pathway through p53, and p53 mutation was usually caused by H. pylori infection.Thus, we propose a new mechanism for malignant transformation induced by H. pylori infection that p53 mutations promote the transformation from senescence to carcinogenesis by CXCR2. This project will firstly confirm H. pylori status in precancerous lesions and cancer of stomach in clinical specimens and animal models. Furthermore, we will prove that p53 mutations control the switch from senescence to cancer. Finally, we will clarify the underlying mechanism of CXCR2 regulated by p53 and associated pathway. This project aims to explore the molecular association between chronic inflammation induced by H. pylori and carcinogenesis of gastric cancer,which may have a major role in early detection and treatment of cancer, as well as the prevention of gastric cancer.

英文关键词： stomach neoplasms;p53 mutation;senescence;Helicobacter pylori;carcinogenesis