TRIM14在非小细胞肺癌发生发展中的作用及机制

非小细胞肺癌（NSCLC）是我国城市人口恶性肿瘤死亡之首，其发病机制还不是很清楚。寻找新的靶标和分子机制有利于其诊疗。我们筛查到一种新的泛素连接酶TRIM14在NSCLC临床标本中的表达显著低于癌旁，而高表达TRIM14能有效抑制NSCLC细胞的生长和迁移。为了探索作用机制，我们利用酵母双杂交筛选到其相互作用蛋白-葡萄糖代谢支路氨基己糖生物合成途径（HBP）的关键限速酶GFAT1。TRIM14能降低GFAT1蛋白而不影响mRNA水平，蛋白酶体抑制剂能阻止该降解作用，且NSCLC细胞的生长依赖于GFAT1和HBP。本项目将进一步深入分析TRIM14与NSCLC临床病理关联性，揭示TRIM14在NSCLC细胞生长、迁移和侵袭中的作用，并阐明TRIM14泛素化降解GFAT1的分子机制，进而明确TRIM14通过抑制HBP调控NSCLC细胞的生物学功能，这将为NSCLC的诊疗提供新的思路和理论基础。

Non-small cell lung cancer (NSCLC) is the top reason for Chinese urban population death of malignant tumors, thus the pathogenesis is not very clear. Searching for new targets and molecular mechanism makes for the diagnosis and treatment of NSCLC. We found that the expression of TRIM14 (a new ubiquitin E3 ligase) in NSCLC clinical tissue specimens is significantly lower than the adjacent tissues. And, overexpression of TRIM14 in lung cancer cells can effectively inhibit the cell growth and migration. In order to explore the underlying mechanism, we screened out GFAT1 as the TRIM14-interacting protein using yeast-two-hybrid systems. GFAT1 is the key rate-limiting enzyme in glucose metabolism branch-amino hexose biosynthetic pathway (HBP). Overexpression of TRIM14 reduced protein level of GFAT1 but not the mRNA, and proteasome inhibitors can stop the degradation. Moreover, the NSCLC cell growth depends on GFAT1 and HBP. In this project, we will further analyze the correlation between TRIM14 and NSCLC clinical pathological features, and elucidate the role of TRIM14 in NSCLC cell growth, migration and invasion. Also, we will clarify the molecular mechanism of GFAT1 degradation via TRIM14 and then reveal the regulatory biological functions on NSCLC cells of TRIM14 through HBP inhibition. It will provide new ideas and theoretical basis for the diagnosis and treatment of NSCLC.