抑癌基因TSC2调控花生四烯酸代谢在结节性硬化相关肿瘤发生发展中的机制研究

Tuberous sclerosis complex (TSC) is a genetic disorder that causes non-malignant tumors to form in many different organs, primarily in the brain, kidney, lung and other organs. TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2. Abnormality of mTOR signaling pathway due to TSC1/2 mutation was considering one of most important reason which cause TSC. Rapamycin and its analogue-mTORC1 inhibitor-have been used in clinical trial with TSC associated tumors in deferent organs. TSC associated tumors regressed somewhat during mTORC1 inhibition therapy but tended to increase in volume after the therapy was stopped. In order to understand the cell event which is TSC1/2 dependent and mTORC1 insensitive, we demonstrate that arachidonic acid metabolism pathway could be an important candidate based on –omics methods. To further uncover the role of arachidonic acid metabolism pathway in TSC, it suggests metabolite of arachidonic acid metabolism like PGE2 could alter the microenvironment and cause development of TSC associated tumor. This study identifies novel finding of rapamycin-insensitive signature of disorder of arachidonic acid metabolism in TSC2-null dells and offer novel hypothesis that TSC2 regulates prostaglandin production and action in TSC. Inhibition of arachidonic acid metabolism pathway will be new strategy for TSC therapy.

结节性硬化症（TSC）是一种的多系统先天性疾病，会在脑部、肾脏及肺等器官出现良性肿瘤，会造成多器官的合并症，导致死亡。TSC1/2的突变目前被认为是其最主要的诱因，下游mTORC1信号通路异常活化是造成肿瘤发生的重要因素。靶向于mTORC1的异常调控是目前的主要治疗手段。mTORC1抑制剂雷帕霉素及类似物已被用于不同受累器官的临床试验中，结果显示对肿瘤负荷有改善作用，但一旦停药后，肿瘤复发。因此，寻找TSC2调控的mTORC1非依赖信号通路，不但可以进一步了解TSC2在肿瘤发生发展中的关键作用，而且为结节性硬化相关肿瘤的治疗提供全新靶标。本课题通过多组学方法，揭示TSC2直接调控mTORC1非依赖的花生四烯酸代谢途径的作用机制，并进一步探讨其下游产物前列腺素等对结节性硬化发生发展的重要作用，详细阐明其相关肿瘤发生发展的机制，进而为抑制花生四烯酸代谢途径治疗结节性硬化提供坚实的理论基础。