项目名称: PDRR1介导JNK3在三阴性乳腺癌紫杉醇化疗DNA损伤应答中的调控机制研究
项目编号: No.81502267
项目类型: 青年科学基金项目
立项/批准年度: 2016
项目学科: 医药、卫生
项目作者: 朱玮
作者单位: 复旦大学
项目金额: 17万元
中文摘要: 三阴性乳腺癌预后不良,化疗耐药性的产生是导致治疗失败的主要原因。申请人前期进行了miRNAs与三阴性乳腺癌紫杉醇耐药的相关研究,发现miR-155在三阴性乳腺癌中的表达明显上调,具有促癌作用并可引起紫杉醇化疗药物抵抗。进一步研究发现miR-155抑制了长链非编码RNA——PDRR1的表达,miR155-PDRR1这一信号轴是一种全新的基于非编码RNA的耐药分子机制。我们的研究证实PDRR1过表达能够增加三阴性乳腺癌细胞对紫杉醇化疗的敏感性,且抑制化疗后DNA损伤应答产物的生成;而c-Jun氨基末端激酶3(JNK3)是PDRR1的相互作用分子。在前期工作的基础上,本项目拟从细胞、分子、动物三个层次展开,解析PDRR1与JNK3的精细相互作用,深入探讨PDRR1介导JNK3在三阴性乳腺癌紫杉醇化疗耐药中的作用机制,明确逆转化疗耐药的有效信号通路和靶点,为三阴性乳腺癌紫杉醇耐药的研究提供新思路。
中文关键词: 乳腺肿瘤;长链非编码RNA;DNA损伤应答;化疗耐药;紫杉醇
英文摘要: Triple-negative breast cancer (TNBC) lacks the three most commonly targeted receptors is most difficult to treatment. To investigate the underlying mechanisms for drug resistance and potential approaches to overcome it is of great significance. We indicated the relationship between miRNAs and paclitaxel-drug resistance of TNBC and found that miR-155 had carcinogenic and drug resistant effect. We further revealed that miR-155 mediated a totally new mechanism of paclitaxel-drug resistance different from previous reports. MiR-155 suppressed a long non-coding RNA-PDRR1, which could mediate JNK3 signaling pathways and DNA damage response effect thereby reversing paclitaxel-drug resistance. Based on these, we subsequently intend to analyze the molecular mechanism about PDRR1 mediates JNK3 signaling pathways leading to paclitaxel-drug resistance of TNBC. Also, we would further analyze the refined interactions between PDRR1 and JNK3, figure out the signaling pathways and targets to reverse paclitaxel-drug resistance.
英文关键词: breast cancer;lncRNA;DNA Damage Response;Resistance to chemotherapy;paclitaxel