METTL10/PIAS3/MITF信号通路在胃癌发生发展中的机制研究

胃癌（GC）是我国高发的恶性肿瘤，幽门螺杆菌（H.pylori）感染是GC的首要发病原因，然而其导致GC发生的机制仍不明确。申请人前期通过代谢组学分析，发现H.pylori感染的GC细胞嘌呤代谢显著增强，进一步RNA-seq分析证实METTL10表达异常升高；预实验证实METTL10在GC中高表达，促进GC细胞增殖和迁移，并介导嘌呤合成代谢关键转录因子MITF的表达；初步机制研究提示METTL10能够结合并甲基化PIAS3，抑制其对MITF泛素化降解；同时，METTL10启动子区存在MITF的结合位点。据此，我们提出假说：METTL10/PIAS3/MITF信号轴及自身环路通过嘌呤代谢调控H.pylori介导的GC发生发展。本项目拟通过分子生物学、动物模型及临床标本验证该假设，研究结论将为H.pylori相关GC的治疗提供靶点及理论依据。

Gastric cancer (GC) is one of the malignant tumors with high incidence in China. H.pylori was considers as the dominant pathogen of GC. However, the underlying mechanism still remains to be determined. We analyzed the metabolomics of GC cell infected with or without H.pylori and found that purine metabolism was comprehensively enhanced. Further RNA-seq analysis revealed that METTL10 was highly expressed. Preliminary data showed that METTL10 was overexpressed in GC, promoted GC cell proliferation and migration. Furthermore, METTL10 facilitated the expression of MITF, a crucial transcriptional factor of purine de novo biosynthesis. Primary mechanic study indicated that METTL10 could potentially interact and methylate PIAS3, which disrupt the ubiquitination of MITF by PIAS3. Meanwhile, MITF could bind to the promoter of METTL10. Collectively, we hypothesized that METTL10/PIAS3/MITF signal pathway plays a critical role in H.pylori mediated GC progression by regulating purine metabolism. By using molecular biology tools, mice model and clinical specimens, we will validate the role of METTL10/PIAS3/MITF feedback loop in GC progression. Our study will provide a novel theoretical basis as well as new drug targets for H.pylori related GC.