CD40信号调控胃黏膜非可控性炎症恶性转化的作用及机制

Nonresloving inflammation play an important role in the malignant transformation of gastrointestinal epithelial. Our preliminary study suggests that CD40 expression gradually increased in the carcinogenesis process of chronic gastritis → gastric mucosal dysplasia → gastric cancer; human-derived CD40L transgenic mice developed spontaneous chronic gastritis and gradually evolved into gastric cancer; the mobilization and activation of myeloid suppressor cells (MDSCs) in the early stage was a key molecular events of gastric carcinogenesis induced by CD40 signaling. Therefore, we propose that CD40 signal is the bond of chronic gastritis and gastric cancer; MDSCs activation in the microenvironment may be a key link in inflammation-induced malignant transformation of gastric stem cells. We intend to carry out the following studies: (1) the establishment of CD40L and gastric stem cells in two-hybrid mouse model; (2) the role and mechanism of MDSCs on the malignant transformation of gastric stem cells mediated by CD40 signal; (3) the dynamic detection of gene expression profiles and signaling pathways in the process of the malignant transformation of gastric stem cell induced by CD40; (4) the intervention role of blocking stem cell signaling pathway on the malignant transformation of gastric stem cells mediated by nonresloving inflammation. Expect to clarify the role and mechanism of CD40 signaling on the malignant transformation of gastric stem cells mediated by nonresloving inflammation, and provide new targets for the early diagnosis, early prevention and early treatment of inflammation-associated tumors.

非可控性炎症在消化道上皮恶性转化中发挥重要作用。我们的前期研究证实，慢性胃炎→胃黏膜不典型增生→胃癌演进中CD40表达逐步增强；人源性CD40L转基因小鼠发展了自发性慢性胃炎，并逐渐演变成胃癌；髓性抑制细胞（MDSCs）早期动员和激活是CD40信号诱发胃癌的关键分子事件。因此，我们提出了CD40信号是慢性胃炎和胃癌的纽带，微环境中MDSCs活化可能是炎症诱发胃干细胞恶性转化的关键环节。本项目拟开展以下研究：（1）建立CD40L与Lgr5蛋白双杂交小鼠模型；（2）探讨MDSCs在介导CD40诱发胃干细胞恶性转化中的作用及机制；（3）动态检测CD40诱发胃干细胞恶性转化过程中基因表达谱和信号通路的变化；（4）探讨阻断干细胞信号通路对非可控性炎症诱发胃干细胞恶性转化的干预作用。期望阐明CD40信号调控胃干细胞在非可控性炎症恶性转化中的作用及机制，为炎症相关性肿瘤的早防、早诊、早治提供新靶点。

胃癌是世界第四最常见的恶性肿瘤,估计每年有934000新病例发病。CD40是肿瘤坏死因子受体的家庭成员,在免疫反应中扮演重要的角色。在这项研究中,首先对CD40激活前后的基因芯片表达结果进行了生物信息学分析，结果表明，PI3K / Akt和JNK/ SAPK信号通路的相关基因,包括JNK1 Gadd45a,Bax,PI3K, Survivin,VEGF均明显表达上调。PI3K基因沉默可以抑制胃癌细胞增殖，迁移，侵袭，阻滞细胞周期于G1期，促进细胞凋亡。研究结果表明，PI3K siRNA可能通过阻断PI3K / Akt信号通路加强CD40诱导的特定抗肿瘤效应。sCD40L和PI3K siRNA是胃癌治疗的一个重要机制。