USP9x/FOXM1相互作用促进TGF-β诱导的肺癌上皮间质转化（EMT）的机制研究

FOXM1 belongs to the large family of Forkhead Box transcription factors. Several studies have shown that FOXM1 plays a key role in lung cancer occurrence and development. It is difficult to thoroughly cure lung cancer because of metastasis. Recently, Epithelial-to-mesenchymal transition (EMT) is considered as one of the important mechanisms regulating lung cancer metastasis. Our earlier study has found that FOXM1 is over-expressed in metastatic lung cancer and A549 cells induced by TGF-β. Further experiments indicated that FOXM1 promoted EMT induced by TGF-β ，and the over-expression of FOXM1 wasn’t due to the regulation of transcription level. The immunoprecipitati- on assay and mass spectrometry showed that there was interaction between FOXM1 and USP9x. Together, we assumed that FOXM1 interacted with USP9x and was deubiquitinated in A549 cells induced by TGF-β. The FOXM1 deubiquitination impels Smad 3 transferred to cell nuclear more efficiently which resulted in intensive activation of the TGF-β signal pathway and finally promoted EMT in lung cancer cells. Verify of this science hypothesis will help to reveal the molecular mechanism of lung cancer metastasis promoting by FOXM1 and provide new target for metastatic lung cancer therapy.

转录因子FOXM1隶属于叉头框家族，它在肺癌的发生和发展中扮演了重要的角色。肺癌难以彻底治愈的主要原因是肺癌的转移。近年来，上皮间质转化被认为是肺癌发生转移的重要分子机制。在前期研究中，我们发现FOXM1在肺转移癌和TGF-β诱导A549细胞中表达升高。进一步实验发现FOXM1对TGF-β诱导的上皮间质转化有促进作用，且FOXM1的蛋白表达水平升高不是转录水平上的调控所致。免疫沉淀和质谱实验发现FOXM1与USP9x存在相互作用，促使我们推测在TGF-β诱导的A549细胞中FOXM1与USP9x相互作用，FOXM1被USP9x去泛素化修饰后蛋白水平升高，使得Smad 3能够更有效地进入细胞核中，导致TGF-β信号转导通路高度活化，促进肺癌细胞的上皮间质转化从而发生转移。本项目对以上科学假说的验证将有助于揭示FOXM1促进肺癌转移的分子机制，为防治肺癌转移提供新的靶点和切入点。

转录因子FOXM1隶属于叉头框家族，它在肺癌的发生和发展中扮演了重要的角色。本项目研究发现FOXM1在肺转移癌和TGF-β诱导A549细胞中表达升高，并且在FOXM1对TGF-β诱导的肺癌细胞上皮间质转化有促进作用。为了探究FOXM1的蛋白表达水平升高不是转录水平上的调控所致，免疫沉淀和质谱实验发现FOXM1与USP9x存在相互作用，促使我们验证在TGF-β诱导的A549细胞中FOXM1与USP9x相互作用，FOXM1被USP9x去泛素化修饰后蛋白水平升高，导致TGF-β信号转导通路高度活化，促进肺癌细胞的上皮间质转化从而发生转移。同时FOXM1的高表达能够有效提升肺癌细胞的上皮间质转化，其机制是由于FOXM1对Twist的转录调控来实现的。对以上科学假说的验证将有助于揭示FOXM1促进肺癌转移的分子机制，为防治肺癌转移提供新的靶点和切入点。在本项目的资助下，我们已经发表论文5篇，培养硕士研究生2名。