SUMO2/3修饰TRAF6促进食管癌血管新生的作用及机制研究

血管新生是食管癌复发转移与预后不良的关键。申请人前期发现：(1) 临床层面，TRAF6在食管癌组织中高表达，是复发的独立危险因素；(2) 功能层面，TRAF6通过HIF1α促进食管癌血管新生；(3) 机制层面，SUMO化修饰关键的类泛素化调节蛋白SUMO2/3能与TRAF6直接结合，SUMO2/3修饰TRAF6与其入核关系密切。据此，申请人提出科学假设：SUMO2/3修饰TRAF6促进其入核直接结合HIF1α，从而促进食管癌血管新生。本研究拟：(1) 通过临床标本验证TRAF6、HIF1α、SUMO2/3的表达及亚细胞分布与食管癌血管新生的相关性；(2) 通过结合位点突变及回复实验等，阐明食管癌中SUMO2/3修饰TRAF6调控HIF1α的具体机制；(3) 通过动物实验，验证TRAF6体内促进食管癌血管新生的作用及机制。本研究的顺利进行将为食管癌的抗血管生成精准治疗提供新的关键分子靶点。

Angiogenesis is an important contributor to esophageal cancer recurrence, metastasis and poor prognosis. Our previous work demonstrated that: (1) Clinically, TRAF6 was overexpressed in esophageal cancer, and the overexpression was an independent risk factor for recurrence; (2) Functionally, TRAF6 could promote angiogenesis of esophageal cancer through targeting HIF1α; (3) Mechanically, SUMO2/3 was proved to bind to TRAF6, and the SUMOylation of TRAF6 was found to be closely associated with the nuclear relocation of TRAF6. Therefore, we raise the hypothesis that TRAF6 SUMOylation by SUMO2/3 relocates TRAF6 to nucleus and TRAF6 promotes esophageal cancer angiogenesis by directly binding to HIF1α. To testify this hypothesis, the present study plans to: (1) investigate the correlation between TRAF6, HIF1α, SUMO2/3 expression/subcellular localization and esophageal cancer angiogenesis through clinical samples; (2) identify the mechanism of TRAF6-HIF1α interaction and the role of TRAF6 SUMOylation by SUMO2/3 via mutation and recovery experiments; (3) validate the role and mechanism of TRAF6 in esophageal cancer angiogenesis in vivo. The results of this study might provide novel targets for anti-angiogenesis therapies in esophageal cancer.