m6A甲基转移酶METTL3促进结直肠癌增殖转移的分子机制研究

It has been demonstrated that m6A RNA methylation plays an important role in tumor development and progression. However, the function and mechanism of m6A in colorectal cancer is still poorly understood. We have found a significant number of m6A-associated somatic mutations in most of cancer types including colorectal cancer in TCGA data. The expression of m6A methyltransferase METTL3 was significantly higher in colorectal tumor tissues compared to normal tissues, which is validated in an independent cohort. The in vivo and in vitro experiments demonstrated that the knock down of METTL3 could inhibit the proliferation and metastasis of colorectal tumor cells. MeRIP-Seq has revealed that the downstream targets of METTL3 were enriched in critical tumor pathway and genes. In this study, we will systematically investigate the molecular mechanism of how METTL3 drive the proliferation and metastasis in colorectal cancer through m6A methylation. This project will provide new markers for the diagnosis and prognosis of colorectal cancers, and new targets for gene therapy.

已有研究报道m6A修饰与肿瘤的发生发展有着密切的关系，但是m6A修饰在结直肠癌的功能和机制尚不清楚。我们前期通过TCGA组学数据分析发现大多数肿瘤包括结直肠癌具有显著数量的m6A相关突变，m6A甲基转移酶METTL3在结直肠癌肿瘤组织的表达显著高于正常组织；在结直肠癌的组织和细胞系验证了METTL3的异常高表达；进一步通过体内体外功能实验表明METTL3的敲降能够抑制结直肠癌细胞的增殖和转移；MeRIP-Seq组学实验结合生物信息分析初步揭示METTL3的下游靶标基因富集在重要的肿瘤相关通路和基因。本研究立足于前期基础,将系统研究METTL3 通过m6A修饰影响结直肠癌增殖和转移的分子机制,并与临床相结合,为寻找结直肠癌新的诊断和预后分子标记物和新的分子靶向治疗靶点提供理论基础。

已有研究报道m6A修饰与肿瘤的发生发展有着密切的关系，但是m6A修饰在结直肠癌的功能 和机制尚不清楚。我们前期通过TCGA组学数据分析发现大多数肿瘤包括结直肠癌具有显著数量 的m6A相关突变，m6A甲基转移酶METTL3在结直肠癌肿瘤组织的表达显著高于正常组织;在结直 肠癌的组织和细胞系验证了METTL3的异常高表达;进一步通过体内体外功能实验表明METTL3的 敲降能够抑制结直肠癌细胞的增殖和转移;MeRIP-Seq组学实验结合生物信息分析初步揭示MET TL3的下游靶标基因富集在重要的肿瘤相关通路和基因。本研究立足于前期基础,将系统研究ME TTL3 通过m6A修饰影响结直肠癌增殖和转移的分子机制,并与临床相结合,为寻找结直肠癌新的 诊断和预后分子标记物和新的分子靶向治疗靶点提供理论基础。