MTA1介导的葡萄糖代谢重编程在结肠癌发生与进展过程中的效应和机制研究

Glucose metabolism reprogramming is one of the most important biological features. In the pilot studies, we first revealed that MTA1 was involved in the glucose metabolism reprogramming while it promotes the development and advancement of colon cancer. Therefore, we proposed that MTA1 promotes colon cancer development and advancement through reprogramming glucose metabolism (e.g. by enhancing the activity of mitochondrial oxidative phosphorylation and glycolysis and suppressing glycogen accumulation). This project focuses on the biological fact that MTA1 is capable of reprogramming glucose metabolism, confirming the effects and mechanism of MTA1 on glucose metabolism by the series of assays and experiments like omics data mining, in vitro biological assay plus in vivo assays in colon cancer animal models as well as assays using human colon cancer tissues. Further, we will construct the molecular regulatory network and locate the key players in the MTA1-mediated glucose metabolism reprogramming. It is the first efforts known to us to reveal the pivot role of MTA1 in modulating glucose metabolism in cancer, in an attempt to complete the theory of glucose metabolism. This proposal is practicable with solid literature support. Based on the novel clues in this project, it is a creative research proposal carrying scientific significance and values for potential translational research.

糖代谢重编程是肿瘤代谢的重要特征之一。我们首次发现MTA1在促进肿瘤发生发展过程中参与糖代谢重编程。基于工作基础，我们提出科学假说：MTA1通过介导肿瘤细胞糖代谢重编程（促进线粒体氧化磷酸化和糖酵解、抑制糖原积累）促进肿瘤的发生与进展。本课题以结肠癌为模型，以MTA1调控肿瘤细胞糖代谢重编程这一事件为主线，先通过组学数据挖掘线索、然后应用体外细胞实验/动物模型体内实验/临床标本验证相结合的方法，证明MTA1基因通过活化肿瘤细胞线粒体氧化磷酸化和糖酵解、抑制糖原积累从而促进肿瘤细胞的恶性表型，并验证MTA1调控糖代谢重编程的关键因子和相关网络，最终建立MTA1调控肿瘤细胞糖代谢重编程促进肿瘤发生发展的理论模型。本课题将首次揭示MTA1在肿瘤糖代谢调控中的枢纽作用，进一步完善肿瘤细胞中能量代谢的调控网络。本研究不但具有充分的理论依据与可行性，还具有显著的创新性、科学意义和潜在的转化研究价值。

肝转移是结直肠癌患者发生的最致命的事件。虽然既往公认肿瘤细胞会倾向Warburg效应，但也发现肿瘤细胞中氧化磷酸化的上调，然而二者间的相互作用机制尚不清楚。在本研究中，我们发现MTA1作为一个新发现的ATP合酶调节剂，通过与ATP5A的相互作用驱动线粒体生物能量代谢重编程，增强氧化磷酸化，从而调节ATP合酶活性和下游mTOR通路促进结直肠癌肝转移。抗癌药物高通量筛选显示MTA1缺失增加了结直肠癌对线粒体生物能量代谢靶向药物mTOR抑制剂的敏感性。抑制ATP5A能以MTA1依赖的方式增强肝转移性肿瘤对西罗莫司的敏感性，其治疗效果在异种移植模型和临床病例中得到了验证。本研究发现了癌症转移中线粒体生物能量重编程的一个新的调节器，并揭示了线粒体氧化磷酸化的上调在肿瘤转移中逆转Warburg效应的新机制。