METTL7B通过m6A甲基化GPX4抑制非小细胞肺癌细胞铁死亡的机制研究

细胞铁死亡与肿瘤发生发展密切相关，然而其调控机制有待深入探索。甲基化转移酶样蛋白家族（METTL）是一类具有甲基化修饰功能的基因，调控多种细胞的功能。课题组前期发现该家族成员METTL7B在非小细胞肺癌中表达显著升高且与预后负相关，近期又通过代谢组测序等发现METTL7B促进GPX4介导的GSH代谢过程并伴随GPX4表达量的增加；METTL7B过表达可逆转RSL3介导的GPX4表达的下调及细胞脂质过氧化水平。据此推测：METTL7B可能通过上调GPX4来抑制肺癌细胞铁死亡，进而促进其存活及生长。本研究拟：采用透射电镜、铁离子浓度检测等实验研究METTL7B对由RSL3介导的铁死亡的影响，阐明METTL7B参与铁死亡通路的调控机制；利用MeRIP、CLIP等技术剖析METTL7B调控GPX4甲基化的分子机制，为揭示其介导的表观遗传学调控机制在铁死亡发生过程中的作用提供理论基础。

Ferroptosis is closely related to tumorigenesis and development, but its regulatory mechanism needs to be further explored. Methyltransferase like protein family (METTL) is a family with methylation modification function, which regulates a variety of cell functions. Recently, metabolism sequencing showed that METTL7B promoted GPX4 mediated GSH metabolism and increased GPX4 expression; overexpression of METTL7B could reverse RSL3 mediated downregulation of GPX4 expression and lipid peroxidation. It is speculated that METTL7B may inhibit ferroptosis of lung cancer cells by up regulating GPX4, and then promote their survival and growth. The purpose of this study is: to study the effect of METTL7B on RSL3 mediated ferroptosis by transmission electron microscopy and iron concentration detection, to clarify the regulatory mechanism of METTL7B involved in ferroptosis pathway; to analyze the molecular mechanism of METTL7B regulating GPX4 methylation by MeRIP and CLIP technology, so as to provide theoretical basis for revealing the role of its mediated epigenetic regulatory mechanism in the occurrence of ferroptosis.