SRC-3激活糖酵解对膀胱癌形成机制研究

Cancer cells mostly rely on glycolysis for energy supply, in which HIF1α plays an essential role. However, the mechanisms underlying HIF1α regulating glycolysis in bladder caner remains unknown. We found that overexpressed SRC-3 in bladder cancer interacts with HIF1α and induces its target genes involved in glycolysis. SRC-3 deficiency impaired bladder cancer cells tumorigenicity, glucose consumption and lactate production under hypoxia. Therefore, we hypothesize that SRC-3 may enhance HIF1α trancriptional activity to mediate glycolysis and eventually promote bladder carcinogenesis. Firstly, we will examine how SRC-3 enhances HIF1α activity. Furthermore, we will examine whether SRC-3 is essential for bladder cancer development through glycolysis. Next, we will confirm SRC-3 and HIF1α target genes involved in glycolysis in clinical samples. At last, we will test whether FGFR/RAS signaling,which is frequently altered in bladder cancer, stimulates SRC-3 activity. Overall, the whole study will reveal how SRC-3 regulates glycolysis in bladder cancer cells, and examine whether SRC-3 is a potential drug target for bladder cancer.

糖酵解是肿瘤细胞获取能量的主要途径，而HIF1α是介导糖酵解的重要转录因子。但是在膀胱癌中糖酵解途径如何被调控的机理了解甚少。我们发现降低过表达的类固醇受体辅助激活因子SRC-3，可抑制膀胱癌癌细胞在低氧情况下糖酵解及肿瘤形成能力。并且SRC-3可与HIF1α结合。据此，本课题的中心假说是膀胱癌中过表达SRC-3通过HIF1α调节FGFR/Ras信号通路介导糖酵解，促进膀胱癌进程。本课题拟首先在膀胱癌细胞模型中探索SRC-3调控HIF1α的转录活性的机制。其次，检测在膀胱癌中特异激活的FGFR/RAS是否是激活SRC-3的上游信号。再者，在BBN化学诱导膀胱癌小鼠模型中验证SRC-3通过调节糖酵解通路活性，对膀胱癌进程起作用。最后，在临床样本中测试SRC-3与HIF1α靶基因表达及上游信号通路的相关性。以上研究将充分阐明SRC-3在膀胱癌中调控糖酵解通路的机制，为治疗膀胱癌提供潜在的药靶。

肿瘤细胞上升的糖酵解途径是肿瘤细胞的代谢异常的一种。在肿瘤发生过程中，缺氧诱导因子HIF1α是一个主要负责调控糖酵解的相关蛋白表达的关键转录因子。该转录因子是如何在肿瘤里调控糖酵解的具体分子机制，现在了解还是不够详细。我们验证了膀胱癌中高扩增/高表达蛋白SRC-3通过直接结合并辅助激活HIF1α，上调由HIF1α调控的糖酵解途径。对于过表达SRC-3的癌细胞采用抑制糖酵解途径中关键酶的活性可以有效抑制癌细胞的增殖。同时我们验证了小分子化合物和厚朴酚能够抑制SRC-3表达，从而抑制其辅助激活上皮向间质转化的转录因子TWIST的活性，下调肿瘤恶性程度。综上所述，我们证明了SRC-3表达水平对于膀胱癌的恶性表型的维持有着重要的促进作用，并且这些恶性表型与肿瘤细胞的糖酵解途径呈现正相关性。无论靶向糖酵解途径关键酶还是通过和厚朴酚下调SRC-3的表达，都可以很好地抑制膀胱癌的恶性程度。