METTL3介导DMC1基因m6A修饰在鼻咽癌中的作用及机制研究

鼻咽癌放疗抵抗是导致肿瘤复发和转移的重要因素，筛选鼻咽癌放疗抵抗相关的分子指标，并明确其在鼻咽癌中的作用分子机制，是预防鼻咽癌复发或转移，及提高鼻咽癌治疗疗效的重要分子靶点。我们前期研究显示：① P300介导的H3K27ac促进METTL3启动子的转录激活，从而促进鼻咽癌细胞中METTL3的表达。② METTL3介导DMC1的mRNA m6A甲基化修饰。③ IGF2BP3识别DMC1的m6A甲基化修饰，从而维持DMC1的m6A修饰后稳定性，并促进其高表达。④ 过表达DMC1增加鼻咽癌放疗抵抗与转移能力等功能密切相关。本项目拟在此基础上，通过体内外功能实验明确DMC1在鼻咽癌中作用及分子机制；同时通过300例临床组织标本明确DMC1在鼻咽癌总生存和无远处转移转移的预测价值，为鼻咽癌的“个体化”治疗提供新的靶点。

Radioresistance is the main cause of recurrence and metastasis in nasopharyngeal carcinoma (NPC), identification key molecular marker related to radioresistance and clarification of its functions and mechanisms in NPC, is an important way to prevent recurrence or metastasis of NPC and a crucial molecular target for improving the therapeutic effect of NPC. Our previous study found that: ① P300 mediated H3k27ac promoted the transcription activation of METTL3, thus upregulating the expression of METTL3 in NPC cells. ② METTL3 mediated the m6A methylation of DMC1 mRNA. ③ IGF2BP3 recognized m6A methylation of DMC1, thus maintaining the transcription stability of DMC1 m6A and upregulating DMC1 expression. ④ Overexpression DMC1 increased radiotherapy resistance and metastasis of NPC. In this study, we will study the functions and mechanisms of DMC1 in NPC in vitro and in vivo. Furthermore, we will detect the DMC1 expression status in 300 NPC patients and examine its prognostic value for overall survival and distant metastasis free survival. Through this research, it could provide a new target for the individualized treatment of NPC.