miR-506多靶点调控HR和β-catenin信号通路对浆液性卵巢癌药物敏感性的影响

项目名称： miR-506多靶点调控HR和β-catenin信号通路对浆液性卵巢癌药物敏感性的影响

项目编号： No.81472761

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： 刘国艳

作者单位： 天津医科大学

项目金额： 72万元

中文摘要： 卵巢癌(OvCa)死亡率高、预后差,患者多死于肿瘤复发和耐药。前期工作通过分析TCGA数据库浆液性OvCa与预后不良间质亚型有关的miRNA调节网络,发现miR-506抑制OvCa上皮-间质转化并促进细胞衰老。课题组对TCGA和INT-Milan数据库的深入分析提示,miR-506是OvCa独立预后因子并与顺铂敏感性相关联,但具体机制不清。本申请以过表达miR-506后的microarray数据为基础,拟通过体外、体内实验和临床病例分析,深入系统地研究miR-506通过多靶点抑制RAD51、EZH2和FOXM1信号,进而调控同源重组修复(HR)和β-catenin信号通路,形成多重复杂功能网络影响OvCa顺铂和PARP抑制剂的敏感性,并评估miR-506/纳米脂质体对OvCa裸鼠移植瘤的化疗增敏作用。通过探讨miR-506调节OvCa药物反应性的机制,为小分子靶向治疗OvCa提供理论依据。

中文关键词： C24_卵巢肿瘤；药物反应性；miR-506；信号通路

英文摘要： Ovarian cancer (OvCa) remains the most lethal gynecological malignancy and the majority of patients with OvCa die from tumor recurrence and chemo-resistance. In previous studies of this project, we analyzed the genomic and epigenetic data of OvCa in TCGA (The Cancer Genome Atlas) using integrated bioinformatics analysis and found that among the miRNA network related to mesenchymal subtype with poor survival,miR-506 could inhibit the epithelial-mesenchymal transition process through targeting SNAI2.We also found that miR-506 could inhibit OvCa proliferation and induce senescence through targeting CDK4/6-FOXM1 axis.We further demonstrated that miR-506 level was associated with progression-free survival and overall survival in TCGA data, which was verified in INT-Milan dataset and miR-506 level was related to cispaltin response. Microarray and western blot results showed that overexpression of miR-506 could down-regulate the mRNA and protein level of RAD51 and EZH2. In this project we plan to further analyze the effect and mechanisms of miR-506 on OvCa sensitivity to cispaltin and PARP inhibitor,which may include targeting RAD51, EZH2 and FOXM1 signaling, and regulating homolougous recombination(HR) and β-catenin signaling pathway through in vitro, in vivo and retrospective clinical experiments. We will evaluate the effects of enhanced sensitivity of miR-506/nanoliposomes in OvCa xenografts mouse model. The results of this work will contribute to understand the multi-targeting regulatory function and mechanism of this new microRNA and supply new potential direction and theoretical basis for OvCa treatment.

英文关键词： ovarian cancer;drug response;miR-506;signaling pathway