当前研究表明泛素连接酶能通过介导自噬相关蛋白的泛素化修饰来抑制自噬，进而促进肿瘤的发生发展。申请人前期工作表明，基因敲除FBXO7、FBXL20和FBXO34可以诱导食管癌细胞发生自噬并抑制细胞增殖。因此，本课题拟以F-box蛋白为切入点，以我国林州地区高发的食管鳞癌为对象，系统开展以下研究：①利用RNA干扰技术，筛选鉴定与食管鳞癌“自噬抑制并促肿瘤增殖”相关的F-box蛋白；②鉴定F-box蛋白调控的自噬相关底物分子；③F-box蛋白介导的底物泛素化对自噬的调控机制；④F-box蛋白、底物及自噬标志物在食管鳞癌临床标本中的表达特征及三者相关性；⑤揭示F-box泛素连接酶调控的自噬在食管鳞癌发生中的作用及机制。项目的实施将有望发现新的F-box泛素化调控通路，阐明食管鳞癌自噬抑制的分子机制，并为设计针对自噬调节分子的肿瘤靶向药物提供新的策略与依据。

Recent studies showed that ubiquitylation of autophagy-related protein could inhibit autophagy and promote tumorigenesis. Our previous work showed that knockdown of FBXO7, FBXL20 and FBXO34 induced autophagy and inhibited esophageal squamous cell carcinoma (ESCC) cell proliferation. The incidence rate of ESCC is higher in Linzhou, Henan, China. Here we regard F-box proteins as a point and take ESCC as the research object for further explore: ①Identification of F-box proteins which inhibits autophagy and promotes cell proliferation in ESCC cells using siRNA library; ②Identify autophagy-related substrate of F-box protein; ③Elucidate the mechanism of F-box-mediated substrate ubiquitination in regulating autophagy; ④Explore the clinical-correlation between F-box，substrate and autophagy marker in ESCC tissues; ⑤Reveal the role and mechanism of F-box-regulated autophagy in ESCC tumorigenesis. In all, our results would find new F-box-regulated autophagy pathway, explore the mechanism of autophagy inhibition in ESCC tumorigenesis and provide novel strategy for drug design targeting autophagy regulators.