EZH2/H3K27me3表观调控胃癌奥沙利铂耐药性分子机制的研究

Gastric cancer carries frequent oxaliplatin chemoresistance and dismal prognosis. The underlying mechanisms remain to be further elucidated. We have examined the protein expression difference between oxaliplatin chemoresistance group and chemosensitive group by proteomics test, and found that the expression levels of EZH2 and Notch1 were positive correlated with oxaliplatin chemoresistance. We also found that Notch1 was epigenetic regulated through the catalyzion of H3K27me3 by EZH2, thereby affecting the oxaliplatin chemosensitivity in GC. In this study, we plan to expand the amount of tissue and serum samples to explore the possible maker for predicting the chemosensitivity, and to study the molecular mechanism of epigenetic regulation of Notch1 by H3K27me3. Furthermore, we aim to investigate other protein expression changes in Notch signaling pathway mediated by EZH2, and the possibility of combination therapy of EZH2 inhibitor and oxaliplatin in GC.

奥沙利铂是治疗胃癌一线化疗药物，其化疗耐药导致治疗失败在临床上较为常见，该现象分子调控机制尚未阐明。申请人前期工作中用蛋白质组学的方法比较了奥沙利铂耐药和敏感患者肿瘤组织中蛋白表达差异，发现EZH2和Notch1的表达水平与胃癌患者的奥沙利铂耐药性呈正相关，并应用Western Blot和免疫组化染色得以验证。在成功诱导的奥沙利铂胃癌耐药株SGC7901/L-OHP上我们发现EZH2是通过改变其催化底物H3K27me3的水平表观调控Notch1的表达，进而影响胃癌对奥沙利铂的敏感性。基于这些工作基础，本项目拟同时研究患者组织与血清中相关蛋白表达水平变化以获得可能的临床预测化疗敏感性指标，深入研究H3K27me3表观调控Notch1影响化疗敏感性的分子调控机制，探索EZH2介导的Notch1改变对Notch通路其它蛋白表达的影响，并初步探索EZH2抑制剂和奥沙利铂联合用药治疗胃癌的可能性。

奥沙利铂是治疗胃癌一线化疗药物，其化疗耐药导致治疗失败在临床上较为常见，该现象分子调控机制尚未阐明。申请人前期发现EZH2和Notch1的表达水平与胃癌患者的奥沙利铂耐药性呈正相关，EZH2是通过改变其催化底物H3K27me3的水平表观调控Notch1的表达，进而影响胃癌对奥沙利铂的敏感性。基于这些工作基础，本项目深入研究H3K27me3表观调控Notch1影响化疗敏感性的分子调控机制，发现了EZH2-H3K27me3-RXR-α-Notch1调控通路，并初步探索了EZH2抑制剂和奥沙利铂联合用药治疗胃癌的可能性。