Mettl3介导的MAPK信号通路m6A甲基化修饰在去势抵抗性前列腺癌形成和耐药中的作用

去势抵抗性前列腺癌（CRPC）机制不明是导致临床上缺乏行之有效治疗手段的原因。RNAm6A甲基化修饰已被证实与多种癌症发生发展相关，但其在CRPC形成及耐药中的机制尚未阐明。课题组前期通过RNAm6A甲基化和转录组测序以及组织芯片、细胞模型证实CRPC中RNAm6A甲基化催化基团Mettl3蛋白水平异常增高与MAPK信号通路的活化及其关键分子HRAS和MAP2K2的RNAm6A甲基化水平改变相关。课题组拟在细胞和动物模型中证实以Mettl3为主的催化基团通过改变HRAS和MAP2K2 mRNA 5’-UTR区域m6A甲基化的修饰水平促进MAPK通路活化的分子机制。最后应用反义寡核苷酸小分子药物体内外验证靶向Mettl3或甲基化修饰位点对恢复抗雄激素信号通路药物的敏感性及阻断CRPC发生的有效性，为CRPC治疗提供新的靶点。

The unknown mechanism of castration-resistant prostate cancer (CRPC) is the reason for the lack of effective treatment in the clinic. RNAm6A methylation modification has been shown to be involved in the development of various cancers, but its mechanism in CRPC formation and drug resistance has not been elucidated. In the early stage of the research group, RNAm6A methylation and transcriptome sequencing, tissue chip, and cell model confirmed the abnormal increase in the level of Mettl3 protein and the activation of MAPK signaling pathway and the key molecules HRAS and MAP2K2 in the CRPC The level of change is related. The research group intends to confirm the molecular mechanism of Mettl3-based catalytic groups to promote the activation of MAPK pathway by changing the modification level of m6A methylation in the 5'-UTR region of HRAS and MAP2K2 mRNA. Finally, the antisense oligonucleotide small molecule drugs were used in vivo and in vitro to verify the effectiveness of targeting Mettl3 or methylation modification sites to restore the sensitivity of anti-androgen signaling pathway drugs and block the occurrence of CRPC, providing new target for CRPC treatment.