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

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.

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。

对于胃癌（GC）控制，转移和化疗抗性是主要挑战，这些过程伴随着各种应激。 已知Ataxin-2-like（ATXN2L）是新发现的应激颗粒的调控分子，但其在癌症中的功能仍然未知。因此，我们想探索ATXN2L的功能，看它是否参与应激相关的癌症恶性生物学行为，并进行临床随访以观察ATXN2L对GC患者生存的影响。结果：ATXN2L表达在GC组织中上调，并且影响总生存时间和复发等不良预后。在GC细胞中，敲除ATXN2L表达并进行功能实验。 ATXN2L通过EMT促进GC细胞迁移和侵袭，但干扰ATXN2L对增殖没有影响。当加入化疗药物奥沙利铂诱导应激时，沉默ATXN2L使GC细胞对奥沙利铂敏感。更有趣的是，我们还发现奥沙利铂反过来促进ATXN2L表达和应激颗粒组装。然后，通过长期奥沙利铂诱导产生两种获得性耐药奥沙利铂抗性细胞株。奥沙利铂耐药株具有升高的ATXN2L水平，而在耐药株中沉默ATXN2L能通过增加活性氧产生和细胞凋亡来逆转奥沙利铂抗性。这些结果表明，ATXN2L不仅是原发性的，也是获得性奥沙利铂耐药的原因。最后，使用生物信息学方法筛选ATXN2L相关信号，并且证实表皮生长因子（EGF）通过PI3K / Akt信号促进ATXN2L表达。阻断EGFR / ATXN2L信号传导可逆转GC细胞奥沙利铂抗性并抑制迁移。结论，ATXN2L促进细胞侵袭性和奥沙利铂抗性，并可以被EGF通过PI3K / Akt信号上调。ATXN2L可能是GC的指标和治疗靶点，特别是对于对于奥沙利铂的化疗抗性的预测和干预有重要价值。