c-Src/HK2对膀胱癌糖代谢和化疗耐药调节机制研究

酪氨酸激酶（c-Src）异常活化参与肿瘤发生及转移过程。前期研究发现：c-Src在膀胱癌肿瘤组织中表达升高，且与膀胱癌患者预后不良相关；但随着肿瘤分级升高c-Src的表达却降低；转录组学和蛋白质组学分析显示c-Src和糖酵解的限速酶（HK2）在膀胱癌化疗药物耐药细胞中表达升高。但c-Src和HK2参与膀胱癌发生发展的分子机制仍不明确。本项目拟在前期研究基础上采用多种分子生物学技术联合计算机辅助模拟方法，深入了解c-Src和HK2在膀胱癌发生发展中的作用；阐明c-Src和HK2相互作用的分子机制、相互作用位点及磷酸化位点；探讨c-Src和HK2相互作用对膀胱癌糖代谢调控机制；明确c-Src和HK2在膀胱癌化疗耐药中扮演角色。本研究结果将从糖代谢及化疗耐药方面为膀胱癌发生发展提供分子机理，为膀胱癌临床靶向治疗提供数据支撑和理论依据。

Abnormal activation of tyrosine kinase c-Src is extensively involved in tumorigenesis and metastasis of many tumors. Our previous work revealed that the expression of c-Src elevated significantly in bladder cancer and expression of c-Src was associated with poor prognosis of bladder cancer patients. Moreover, the expression of c-Src decreases with the increase of tumor grade. RNA-seq and proteomics analysis suggest that expression of c-Src and the glycolysis rate-limiting enzyme HK2 increased in chemotherapy drug-resistant bladder cancer cells. However, the molecular mechanism of c-Src and HK2 involved in the development of bladder cancer is still to be elucidated. Herein, in this project, multiple biological techniques combined with computer-aided molecular dynamics simulation method will be applied to investigate the role of c-Src and HK2 in the development of bladder cancer; to elucidate the interaction mechanism, binding site and phosphorylation site of c-Src and HK2 interaction; to explore the regulatory mechanism of the c-Src-HK2 interaction towards glucose metabolism of bladder cancer; to discovery the the role of c-Src and HK2 in chemotherapy resistance of bladder cancer. The result of this project may provide molecular mechanism for the development of bladder cancer from the perspective of glucose metabolism and drug resistance, and provide data support and theoretical basis for clinical targeted treatment of bladder cancer.