表观抑制子EZH2通过维持肾癌干细胞样特性参与舒尼替尼抵抗的机制研究

项目名称： 表观抑制子EZH2通过维持肾癌干细胞样特性参与舒尼替尼抵抗的机制研究

项目编号： No.81472376

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郭剑明

作者单位： 复旦大学

项目金额： 52万元

中文摘要： 组蛋白赖氨酸N-甲基转移酶EZH2异常活化所导致的表观遗传学异常在包括肾癌在内的诸多肿瘤发生发展中发挥重要作用。我们前期研究发现高表达EZH2与肾癌不良预后相关，并通过抑制E-cadherin的表达促进上皮间质转化（EMT）（BJU INT 2014; PLOS ONE 2013）。舒尼替尼作为晚期肾癌一线药物与干扰素相比显著延长晚期肾癌无进展生存期，然而转移性肾癌对舒尼替尼反应率较低，为了更好的个性化分子靶向治疗与减少治疗抵抗，舒尼替尼治疗抵抗的分子机制与克服策略急待阐明。已有研究证实上皮间质转化与肿瘤干细胞特性和耐药发生密切相关。我们前期发现EZH2可诱导肾癌细胞抵抗舒尼替尼诱导的细胞凋亡。本申请项目拟在上述工作基础上，从表观遗传学角度出发，研究EZH2通过肾癌干细胞样特性参与舒尼替尼抵抗的分子机制与克服策略，为开发针对EZH2高表达的肾癌分子靶向治疗临床研究和药物开发奠定基础。

中文关键词： C12_肾；肾盂；输尿管肿瘤；EZH2；耐药；肿瘤干细胞；上皮间质转化

英文摘要： Epigenetic abnormalities caused by abnormal activation of EZH2 play an important role in many tumors development including renal cell carcinoma. Our previous study found that high expression of EZH2 correlates with poor outcome in renal cell carcinoma and promotes epithelial- mesenchymal transition (EMT) via inhibiting the expression of E-cadherin. (BJU INT 2014; PLOS ONE 2013)Sunitinib is a multitargeted inhibitor of receptor tyrosine kinases(RTK). Sunitinib improved progression-free survival (PFS) compared to treatment with interferon, while the response rate was very little and majority patients eventually developed therapeutic resistance. Along with increasingly widespread sunitinib administration against mRCC, molecular mechanism and overcome strategies for sunitinib treatment therapeutic resistance await urgent elucidation for personalized molecular-targeted therapeutic to fortify efficacy and overcome resistance. It has been confirmed EMT is closely related to the characteristics of cancer stem cells and drug resistance.We found that EZH2 can induce renal cancer cell resistance to sunitinib -induced apoptosis.The project intends to apply on the basis of the above work,from the perspective of epigenetics to study that EZH2 participates in sunitinib resistance via renal cell carcinoma stem cell maintenance and lay the foundation for the molecular -targeted therapeutic and drug development.

英文关键词： RCC;EZH2;resistance;CSC;EMT