共济失调素-2样蛋白（ATXN2L）促进胃癌发生发展的作用和分子机制研究

目前关于共济失调素-2样蛋白（ATXN2L）的研究甚少，在肿瘤领域更无文献可查。我们前期发现ATXN2L高表达的胃癌患者预后不良，因而好奇：ATXN2L是否促进胃癌发生发展，背后机制又是什么？另一方面，表皮生长因子（EGF）及其受体家族（HER）的激活能触发多条胃癌生长信号通路，是胃癌的研究热点；我们通过生物信息学分析得出：EGF可借助转录因子E2F促进ATXN2L表达，ATXN2L能调控EGF/HER信号。随后预实验也证实：EGF上调胃癌细胞ATXN2L表达，沉默ATXN2L能抵抗EGF的促增殖作用，ATXN2L增强EGF/HER下游多个信号分子表达。故假设：ATXN2L与EGF/HER相互正反馈调控，促进胃癌发生发展，进而影响预后。本项目将借助临床分析、动物和细胞功能实验及分子生物学实验等手段，首次在肿瘤领域就ATXN2L与胃癌的关系开展研究，探明ATXN2L促进胃癌进展的作用和机制。

Currently ataxin-2 like (ATXN2L) is seldom studied, and its role in cancer is even undocumented. Our preliminary exploration discovered that ATXN2L was highly expressed in gastric cancer (GC) tissue and indicated adverse prognosis. This inspired us to ask whether ATXN2L promotes GC tumorigenesis and what is the underlying mechanisms. On the other hand, epidermal growth factor (EGF) and its receptors (HER) activation are known to trigger multiple signaling pathways promoting GC growth. As demonstrated by our bioinformatics analysis, ATXN2L may be upregulated via transcription factors E2F activation, and ATXN2L may feedback-regulate EGF/HER signaling. Our preliminary experiments also showed that: ATXN2L was upregulated by EGF; silencing ATXN2L diminished the EGF-induced proliferation; ATXN2L upregulated the downstream signaling molecules of EGF/HER. Therefore, we hypothesize that there might be a positive feedback loop between EGF/HER and ATXN2L, which promotes GC growth and consequently leads to adverse prognosis. Current project will be carried out by means of clinical analysis, in vivo and in vitro functional experiments and molecular biological experiments. The results of this project would provide the first evidence of ATXN2L in tumorigenesis, and clarified the mechanism how EGF and ATXN2L promotes GC growth. Finally, this project is expected to verify ATXN2L as the novel therapeutic target for GC.