胃癌严重危害人类健康，N-亚硝基类化合物为其主要危险因素，其中MNNG是代表性致癌物质，但其所致胃癌分子机制尚未完全阐明。表观遗传调控在环境化学致癌中起到关键作用，RNA甲基化m6A修饰参与的表观遗传机制成为新的突破。本项目前期研究发现，m6A甲基化酶METTL3可能在MNNG诱导胃粘膜上皮细胞恶性转化中发挥重要作用，且可能通过对miRNA的调控影响胃癌发生进程。因此，本项目拟通过MNNG恶性转化细胞模型和METTL3基因敲除动物模型，深入阐明METTL3介导的m6A修饰调控关键miRNA在MNNG致胃癌发生发展中的作用和分子机制；并进一步通过胃癌高发区及多中心人群研究，探讨METTL3相关分子作为胃癌人群生物标志的可能。研究从m6A RNA甲基化调控的新角度出发，为深入阐明胃癌的环境化学致癌作用机制，寻找有效生物标志及提出新的防治措施提供科学依据。

Gastric cancer is the common malignant tumor with a risk to human health. N-nitroso compounds are the main risk factors of gastric cancer. Among them MNNG is one of the representative carcinogen, but the molecular mechanism of MNNG-induced gastric cancer has not been fully elucidated. Epigenetic regulation plays a key role in environmental carcinogens-induced tumors, and the epigenetic mechanism involved in RNA methylation m6A modification has become a new breakthrough. Our previous study found that m6A methylase METTL3 might play an important role in the malignant transformation of gastric epithelium cell induced by MNNG, and may influence the development of gastric cancer through the regulation of miRNAs. Therefore, the purpose of our study is to elucidate the role and molecular mechanisms of METTL3-mediated m6A modification regulating key miRNAs in the development of gastric cancer induced by MNNG through MNNG malignant transformation cell model and METTL3 gene knockout animal model. In addition, through population-based studies of multicenter cooperation in high-incidence areas of gastric cancer to explore the possibility of METTL3-related molecules as biomarkers for gastric cancer. From a new perspective of m6A RNA methylation regulation, this study provides scientific basis for further elucidating the mechanism of environmental chemical carcinogenesis of gastric cancer, searching for effective biomarkers and putting forward new preventive and therapeutic measures.