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

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.

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。

胃癌是世界上常见恶性肿瘤之一，我国大部分胃癌病人在确诊时已是中晚期，治疗效果不佳， 提高胃癌早期诊断率及降低胃癌发病率，是目前急需解决的问题。幽门螺杆菌感染导致的炎症可能是胃癌发病的重要原因之一，我们上一个国自然课题的研究发现，AEG-1与TLR4形成的正反馈通路导致胃癌细胞在幽门螺杆菌的感染下发生不可控炎症，并且与胃癌的不良预后相关。在本课题中，我们进一步探讨幽门螺杆菌诱导的炎症及细胞衰老在胃癌发生发展中的作用。我们发现，细胞衰老在胃癌的癌前病变中是常见现象，且以萎缩性胃炎中衰老细胞比例最高，而幽门螺杆菌感染促进了胃黏膜的衰老。幽门螺杆菌通过注射CagA蛋白进入胃黏膜细胞，上调NFKB1，进一步激活CXCR2和野生型p53形成的正反馈通路，该通路持续性激活并促进细胞衰老。CXCR2具有双刃剑作用，当p53突变失去抑癌功能后，CXCR2反而发挥促癌作用，而且某些突变型p53蛋白还能通过CXCR2相关通路促进胃癌的进展。我们同时也发现，肿瘤相关淋巴管内皮细胞能分泌CXCR2配体CXCL1，CXCL1与CXCR2结合后进一步激活integrinβ1/FAK/AKT通路促进胃癌的淋巴转移，这进一步说明了CXCR2的促癌作用。萎缩性胃炎是胃癌重要的癌前病变之一，我们发现幽门螺杆菌通过CXCR2介导的胃黏膜上皮过度衰老可能是导致萎缩性胃炎的重要原因，抑制CXCR2可能抑制萎缩性胃炎的发生，而且，在突变型p53中，CXCR2发挥促癌作用，抑制CXCR2可抑制肿瘤进展，因此，我们认为CXCR2可作为胃癌预防及治疗的一个潜在靶点。我们在幽门螺杆菌感染胃黏膜的动物模型中证实，使用CXCR2抑制剂抑制了胃黏膜细胞的衰老及粘膜的萎缩，并且延缓了肠上皮化生和不典型增生的进展。因此，我们在本国自然基金的资助下，进一步阐明了幽门螺杆菌致癌的机制，并初步证明CXCR2可作为胃癌预防和治疗的潜在靶点。