类泛素小分子NEDD8调控GLUT5介导的果糖代谢促肺腺癌增殖转移的机制研究

肺腺癌是肺癌最常见的病理类型，靶向药物治疗后不可避免地出现药物耐受，以至病情进展。申请者前期研究证实类泛素小分子NEDD8可通过增强CRLs结合底物能力调控肺腺癌增殖转移，且据报道SCF-FBXL17/BACH1是CRLs发挥转录调控作用的重要通路；进一步发现敲除NEDD8可以显著下调GLUT5的表达，而GLUT5的促肿瘤功能与果糖代谢密切相关。因此NEDD8可能通过调节GLUT5影响果糖代谢调控肿瘤发生发展，但具体机制尚未阐明。我们提出假说：NEDD8可通过活化SCF-FBXL17泛素降解转录抑制因子BACH1调控GLUT5转录以影响果糖代谢，靶向NEDD8可阻断肿瘤的果糖代谢途径。本课题拟研究1.干预NEDD8表达后果糖代谢的改变；2.NEDD8对GLUT5具体转录调控机制；3.NEDD8对AMPK/mTORC1信号通路影响。为肿瘤果糖代谢研究提供新的机制，为肺腺癌靶向治疗提供新靶点。

Lung adenocarcinoma is the most common pathological type of lung cancer. Drug tolerance are inevitable after targeted drug therapy. Our previous research confirmed that the Neural precursor cell Expressed Developmentally Downregulated protein 8 can regulate the proliferation and metastasis of lung adenocarcinoma by enhancing the ability of CRLs binding substrate, and it is reported that scf-fbxl17 / Bach1 is an important pathway for CRLs to play a role in transcriptional regulation; it was further found that the knockout of Nedd8 can significantly reduce the expression of GLUT5, and the tumor promoting function of GLUT5 is closely related to fructose metabolism. Therefore, Nedd8 may affect fructose metabolism by regulating GLUT5, but the specific mechanism has not been clarified. We propose the hypothesis that Nedd8 can regulate GLUT5 transcription by activating scf-fbxl17 to ubiquitinatedly degradate transcriptional inhibitor Bach1, and target Nedd8 can block the fructose metabolism pathway of tumor. In this research, 1. Changes of fructose metabolism after intervention of Nedd8 expression; 2. Specific transcriptional regulation mechanism of GLUT5 by Nedd8; 3. Effect of Nedd8 on AMPK / mTORC1 signaling pathway. It provides a new mechanism for the research of tumor fructose metabolism and a new target for the targeted treatment of lung adenocarcinoma.