pSTAT3-NFκB信号协同lncRNA BANCR调控肾癌细胞磷酸戊糖代谢重编程的作用及分子机制

肾细胞癌是泌尿系统中致死率较高的恶性肿瘤，具有高转移率、放化疗耐药、预后差等特点。因此，阐明肾癌发病机制是其研究的关键。我们发现，G6PD异常活化及其调控的磷酸戊糖代谢重编程可能与肾癌发生密切相关。本课题将通过临床标本检测，确定上述代谢异常与肾癌发生发展、恶性程度及治疗预后的相关性。通过细胞和动物模型的建立，明确肾癌中代谢重编程是否通过影响ROS水平而调控CyclinD1、MMP2表达，从而促进肿瘤细胞增殖和迁移侵袭；代谢重编程中ROS积累是否可诱导pSTAT3-NFκB复合体形成并促进G6PD转录；同时，肾癌中是否存在抑癌lncRNA BANCR表达的降低，并解除了在翻译后水平对G6PD二/四聚化及酶活性的抑制，从而共同导致了G6PD调控的以磷酸戊糖代谢为核心的重编程现象。本课题是研究肿瘤代谢重编程与信号转导及lncRNA的新视角，将为肾癌的基础研究和临床靶向治疗提供新的线索。

Renal cell carcinoma (RCC), which is a high fatality rate of malignant tumor in urinary system, has the characteristics of high transfer rate, radiation and chemotherapy resistance, poor prognostic, etc. Therefore, the pathogenesis study is the critical work for RCC research. In the previous study, we found that the abnormal activation of G6PD and dysregulation of pentose phosphate metabolic reprogramming might be closely related to the occurrence of RCC. In the present study, we will determine the correlation between this metabolic reprogramming and the development, malignant degree, therapeutic resistance or prognosis of RCC by clinical specimen analysis. Through cell and animal model, we will demonstrate that metabolic reprogramming in RCC could promote CyclinD1 and MMP2 expression by ROS up-regulation, thereby promoting tumor cell proliferation and migration. The accumulation of ROS level via metabolic reprogramming may induce pSTAT3-NFκB complex formation and promote G6PD transcription. Meanwhile, the down-regulation of anti-cancer lncRNA BANCR expression might revive the G6PD dimerization/four polymerization and enzyme activity at post-translational level. These reasons may lead to G6PD dysregulation and pentose phosphate metabolism reprogramming in RCC. Taken together, our project is a new perspective for the study of tumor metabolic reprogramming, signal transduction and lncRNA, and may provide new clues for basic and clinical researches of target therapy.