LMP2A通过泛素化调控ATGL并促进鼻咽癌细胞恶性生物学行为的机制研究

前期研究中我们发现，脂肪代谢异常是鼻咽癌值得深究的特征之一。我们还发现EB病毒编码的潜伏膜蛋白LMP2A可负向调控甘油三酯分解的限速酶—ATGL，促进脂滴堆积，改变鼻咽癌细胞脂肪代谢谱，并藉此加速细胞的迁移能力。且ATGL在鼻咽癌中普遍转录和表达下调，ATGL低表达与患者较差的预后相关。这些线索提示：ATGL的失活可能是LMP2A影响脂肪代谢并调控鼻咽癌细胞恶性生物学行为的关键节点。在这些前期工作基础上，本项目拟通过系列肿瘤生物学实验，探究LMP2A通过泛素连接酶G2E3介导ATGL降解，导致脂肪代谢重编程并促进鼻咽癌细胞转移和增殖等恶性生物学行为的可能分子机制。本项目将探讨EB病毒通过调控细胞脂肪代谢重塑而促癌这一潜在的致癌机制。研究结果将为其他EB病毒相关恶性肿瘤乃至病毒相关恶性肿瘤提供参考，也可为鼻咽癌的个体化诊治提供新的生物标志物和新的分子靶标。

In our previous study, we discovered that dysregulated lipid metabolism is one of the most important characteristics of nasopharyngeal carcinoma (NPC) which worths intensive research. Importantly, we found the latent membrane protein 2 (LMP2A) encoded by Epstein-Barr virus (EBV) negatively regulates expression of triglyceride hydrolysis lipase--adipose triglyceride lipase (ATGL) in NPC cells. Subsequently, lipid droplets accumulation, as well as lipid metabolism profiles alteration were observed, thereby accelerating cell migratory capacity. Besides, ATGL is commonly downregulated in NPC and is remarkably correlated with worse outcome of NPC patients. These clues suggest that the inactivation of ATGL may be the key node for LMP2A to affect lipid metabolism and regulate the malignant behaviors of NPC. In the present study, we intend to explore whether the degradation of ATGL was mediated by LMP2A via a ubiquitin-protein ligase G2E3, and how ATGL reprograms the cellular lipid metabolism and promotes the malignant behaviors in NPC. Our discovery might reveal a novel mechanism of EBV carcinogenesis by manipulating cellular lipid metabolism and provide a novel biomarker for personalized treatment of NPC. Furthermore, the outcomes of this study may shed light on other EBV infection-related malignants and so far as to other virus-related cancers.