Septin5通过GFPT1调控甘露糖代谢重编程在肾透明细胞癌中的功能及分子机制研究

肾透明细胞癌（ccRCC）进展迅速、预后不良、治疗特异性差，原因在于其发生发展机制仍未被阐明。因此，揭示其特异性分子机制是ccRCC研究的关键。前期研究发现，ccRCC中存在甘露糖摄入和代谢异常，同时，在肿瘤中通过相互作用和异常表达发挥功能的Septin家族因子Septin5也出现高表达。本项目将明确ccRCC中是否存在甘露糖代谢重编程，及其与ccRCC发生发展的相关性。其次，确定Septin5是否与甘露糖代谢的重要过程己糖胺生物合成途径的关键酶GFPT1相互作用而抑制其活性，进而降低P53糖基化及其稳定性，同时改变通过底物正向调节作用促进糖酵解，为ccRCC细胞提供更多物质和能量来源。通过上述机制，甘露糖代谢发生重编程并促进ccRCC发生发展。本项目从多组学分析代谢重编程出发，是基因表达产物与代谢调节相结合的研究新视角，其顺利完成将为ccRCC诊疗发展提供新线索。

Clear cell renal cell carcinoma (ccRCC) has the characteristics of rapid progress, poor prognosis rate and lack of specific therapy which is caused by unclear mechanism of tumorigenesis and development. Therefore, understanding the mechanism of ccRCC tumorigenesis and development and revealing its specific characteristics are the key for ccRCC research. In the preliminary research, intake and metabolic reprogramming of mannose can be found in ccRCC. While Septin5, a member of Septin family which always excute oncological function via abnomal expression and interaction, is also observed in ccRCC. In the present study, it will be verified that whether mannose metabolism is reprogrammed in ccRCC and the correlation between mannose metabolic reprogramming and ccRCC tumorigenesis and development will also be unraveled. Subsequently, the underlying mechanism will be demonstrated that Septin5, inhibits GFPT1 activity, which is the key enzyme of hexosamine biosynthesis pathway, a critical mannose metabolic pathway, by interacting with it to decline P53 GlcNacylation, and finally reduces P53 protein stability. Meanwhile, this process will change mannose metabolic flux, promotes glycolysis via substrate positive regulatory effect, and finally provide more materials and energy for ccRCC cells. Mannose metabolic reprogramming will promote ccRCC tumorigenesis and development based on the above mechanisms. Taken together, this study starts from investigation of metabolic reprogramming by multi-omics analysis, which is a new perspective for the integrated research of gene expression products and metabolites. The results and achievements of this study will provide new clues for the precise diagnosis and treatment of ccRCC.