线粒体蛋白TMEM126A抑制乳腺癌转移的机制研究

Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial proteins in metastasis, the major cause of cancer death. In the present study, we found that TMEM126A is lower expression in breast cancer cell lines such as MDA-MB-231, MDA-MB-231HM and MDA-MB-231BO with strong metastasis potency. Our preliminary experiments demonstrated that overexpression of TMEM126A inhibit migration of cell lines MDA-MB-231 and MDA-MB-231HM. Results above indicated that TMEM126A was likely to play an important role in metastasis of breast cancer. This study aims to unveil the mechanism of TMEM126A involving in breast cancer metastasis, the key points which TMEM126A modulates and the molecular pathways participating. Furthermore, we hope to find how TMEM126A clinically relates to breast cancer metastasis, survival rate and prognosis. This research is helpful to explore the relevance between mitochondria and breast cancer metastasis and cast light on a potential new target molecule which may be a potent diagnostic marker for breast cancer.

乳腺癌严重危害女性健康，线粒体蛋白在乳腺癌发生发展中的作用报道很少，其与乳腺癌转移的研究报道更少。我们前期工作首次发现，线粒体蛋白TMEM126A在转移能力强的乳腺癌细胞中低表达，而过表达TMEM126A能显著降低细胞的迁移能力。前期结果提示，TMEM126A可能在抑制乳腺癌转移方面发挥重要作用。本项目拟深入研究TMEM126A降低乳腺癌转移的具体机制，找出TMEM126A调控的可能信号通路；探索TMEM126A与乳腺癌转移，病人生存率，预后等指标之间的临床规律。本项目有助于进一步解析线粒体蛋白与乳腺癌转移的关系，促进从线粒体蛋白寻找乳腺癌生物标志物的研究；为乳腺癌的临床治疗提供新思路，对于指导临床治疗乳腺癌具有实际的应用价值。

TMEM126A为线粒体内膜定位的跨膜蛋白，目前并无研究报道其在肿瘤中的作用。该项目利用SILAC定量蛋白质谱筛选原发肿瘤细胞和转移细胞中差异表达的线粒体蛋白，结果显示TMEM126A在转移能力强的细胞中呈现相对低表达。进而在乳腺癌细胞及组织中也证实TMEM126A在转移较强的细胞及组织中表达相对低。过表达TMEM126A能够显著抑制乳腺癌细胞在体内体外的转移能力，而干扰其表达能显著促进细胞的转移能力。进而，我们利用RNA-seq技术寻找可能的下游机制，结果提示，TMEM126A可能与MAPK、细胞局部粘附信号通路、细胞骨架重排、TGFβ信号通路等相关。进一步验证发现，TMEM126A可能通过抑制TGFβ信号通路中p-Smad3进而抑制EMT及细胞骨架等来抑制细胞的转移能力。同时，干扰TMEM126A能显著促进线粒体ROS的产生，降低细胞的膜电位，打乱线粒体代谢的平衡。最后，在人乳腺癌标本中检测也证实TMEM126A的低表达与乳腺癌的预后差相关。总的来说，我们的研究证实干扰TMEM126A能诱导线粒体功能紊乱，进而激活p-smad3诱导的细胞间质转化和细胞骨架重排，进而促进细胞的转移。线粒体基因TMEM126A可能作为一个新的乳腺癌抑转移基因，该项目的研究结果将为乳腺癌的临床诊断和预后提供理论依据。