胃癌发病、死亡率高居恶性肿瘤前三位，寻找控制其发生的重要基因有助于其防治。我们前期新发现了一个胃癌抑癌基因MDGA2，它与DMAP1直接结合，依赖DMAP1来抑制胃癌生长。目前DMAP1与胃癌等其它常见肿瘤的相关分子机制尚不清楚。预实验发现胃癌中DMAP1低表达，过表达DMAP1能明显抑制胃癌细胞增殖，因此我们设想它是一个抑癌基因。此外，MDGA2在胃癌中由于启动子超甲基化而失活，而DMAP1是DNA甲基化转移酶1相关蛋白1，因此我们设想DMAP1在MDGA2启动子甲基化中也起作用：MDGA2与DMAP1结合，阻碍DMAP1与DNMT1结合，从而抑制MDGA2发生启动子甲基化。本课题将研究：DMAP1作为胃癌分子诊疗标志物的可行性；其对细胞周期、凋亡、迁移及侵袭能力的影响；DMAP1在MDGA2启动子甲基化中的作用及其机制。这对深入理解胃癌发生发展的机制、探寻肿瘤治疗新靶点具有重要意义。

Gastric cancer is one of the leading causes of cancer related deaths in China, which severely threatens the human health. However, the molecular mechanism of gastric cancer is still unclear. To investigate genes which are crucial for gastric cancer tumorigenesis is very helpful for its diagnosis and prognosis. Our previous study elucidated the role of a novel tumor suppressor gene, MDGA2, in gastric cancer. .DMAP1 was found to interact directly with MDGA2 in gastric cancer. Then, depending on DMAP1, MDGA2 suppressed gastric cancer. Nevertheless, the role of DMAP1 in common cancer especially in gastric cancer remains largely uncharacterised currently..Our preliminary data showed that DMAP1 was downregulated or silenced in gastric cancer. Further study demonstrated that DMAP1 suppressed gastric cancer cell growth, as evidenced by cell viability and colony formation assays in AGS and BGC823 cells transfected with DMAP1. This indicates that DMAP1 may act as a tumor suppressor in gastric cancer. .Additionally, our previous study showed that MDGA2 was commonly silenced in gastric cancer cells and primary gastric cancers due to its promoter hypermethylation. DMAP1, which has been named DNA methyltransferase 1 associated protein 1, may play an important role in the promoter hypermethylation of MDGA2. The process of this is proposed that the interaction of MDGA2 and DMAP1 competitively inhibit the interaction of DMAP1 and DNMT1, which subsequently suppress the promoter hypermethylation of MDGA2..In this study, we will evaluate DMAP1 expression as a biomarker in the clinical application on a large-scale cohort of gastric cancer tumor samples, observe its function as a tumor suppressor in vitro and in vivo, and explore the molecular mechanism of its role in the promoter hypermethylation of MDGA2 through 1) clarifying that MDGA2 is downregulated by promoter hypermethylation in gastric cancer cells and primary gastric tumours; 2) demonstrating the interaction of MDGA2 and DMAP1; 3) confirming the interaction of DMAP1 and DNMT1; 4) explaining that the interaction of MDGA2 and DMAP1 competitively inhibits the interaction of DMAP1 and DNMT1; 5) elucidating that, depending on DMAP1, the expression of DNMT1 contributes to the promoter hypermethylation of MDGA2; 6) clarifying that both DNMT1 and DMAP1 make contributions to the promoter hypermethylation of MDGA2 which is proposed to be downregulated or silenced consequently in gastric cancer. This study will provide a comprehensive understanding of the mechanism of the occurrence and development of gastric cancer. This is also theoretically and practically important for the identification of new markers and therapeutic targets for diagnosis and treatment of gastric cancer.