DNMT3A表观调控AATK1抑制CDC25B磷酸化介导胃癌生长转移的分子机制

AATK1是一种参与蛋白磷酸化修饰的酪氨酸激酶，其调控胃癌发生发展的分子机制不明。前期工作结合生信分析表明，AATK1在胃癌中低表达，且与DNMT3A表达显著负相关，利用5’-Aza-dC处理胃癌细胞引起AATK1表达上调，过表达AATK1可促进CDC25B磷酸化进而抑制胃癌细胞的增殖、迁移侵袭，促进细胞凋亡。提示DNMT3A表观调控AATK1，抑制CDC25B磷酸化调节胃癌的生长转移。本研究拟收集胃癌样本结合常规细胞分子生物学技术分析DNMT3A、AATK1和CDC25B表达的临床意义；利用BSP、ChIP、Co-IP、质谱分析等技术探索DNMT3A表观调控AATK1及AATK1磷酸化CDC25B对胃癌生长转移的分子机制；荷瘤小鼠模型在体验证DNMT3A/AATK1/CDC25B轴对胃癌进程的影响，并分析其与胃癌患者的临床相关性。研究结果将为AATK1在胃癌诊断与治疗中的应用提供新视角。

AATK1 is a tyrosine kinase involved in protein phosphorylation modification, and its molecular mechanism regulating the progression of gastric cancer (GC) is unknown. Previous study combined with bioinformatics analysis showed that AATK1 was down-regulated in GC and has a significant negative correlation with the expression of DNMT3A. Treatment of GC cells with 5’-Aza-dC caused AATK1 expression to be up-regulated. Overexpression of AATK1 inhibited the proliferation, migration and invasion of GC cells and induced cell apoptosis by promoting the phosphorylation of CDC25B. It is suggested that DNMT3A regulate the growth and metastasis of GC via inhibiting CDC25B phosphorylation by epigenetic regulating AATK1. In this study, we will collect GC samples and analyze the clinical significance of the DNMT3A, AATK1 and CDC25B expressions in combination with cellular and molecular biological techniques. Next, we will explore the molecular mechanism of DNMT3A epigenetic regulating AATK1 and CDC25B phosphorylation on the growth and metastasis of GC by using BSP, ChIP, Co-IP,mass spectrometry and so on. Finally, we will validate the effects of DNMT3A/AATK1/CDC25B axis on the progression of GC in vivo with nude mouse model, and analyzes its clinical correlation with GC patients. The results will provide a new perspective for the application of AATK1 in the diagnosis and treatment of GC.