NDRG2介导泛素化蛋白降解途径在抑制HER2阳性乳腺癌耐药中的作用及机制研究

项目名称： NDRG2介导泛素化蛋白降解途径在抑制HER2阳性乳腺癌耐药中的作用及机制研究

项目编号： No.81472598

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： 李南林

作者单位： 中国人民解放军第四军医大学

项目金额： 72万元

中文摘要： HER2是乳腺癌治疗的有效靶点。HER2靶向治疗已是HER2+乳腺癌治疗的主要手段，但是抗HER2治疗容易产生耐药，其原因之一是HER2蛋白过度表达。NDRG2是一个新的抑癌基因，可与p53形成信号环路，在多种肿瘤中发挥抑瘤作用，但是有关NDRG2与肿瘤耐药的研究还未见报道。我们前期实验发现与亲本细胞相比，HER2+乳腺癌耐药细胞NDRG2表达显著下调，上调NDRG2可增加耐药细胞的药敏性。深入研究发现NDRG2/p53信号环路可有效上调E3泛素连接酶Siah1的水平，从而调控HER2蛋白降解。因此，我们认为NDRG2在抑制HER2+乳腺癌耐药中发挥作用，NDRG2/p53信号环路上调Siah1介导的泛素通路调控HER2蛋白的降解，抑制肿瘤耐药性。本研究拟从细胞功能、分子机制和临床意义等层面研究NDRG2在抑制HER2+乳腺癌耐药中的作用和分子机制，对优化现有的抗HER2治疗策略具有意义。

中文关键词： C21_乳腺肿瘤；HER2；NDRG2；耐药；泛素化

英文摘要： HER2 is a therapeutic target of breast cancer and HER2 targeted therapy has been the primary treatment of HER2-positive breast cancer. But the anti-HER2 therapy is prone to be resistant and one of drug resistant reasons is HER2 protein overexpression. NDRG2 is a new tumor suppressor gene and plays an inhibitory role in a variety of tumors by forming a loop with p53, but the research of NDRG2 on drug resistance has not been reported yet. Our privious study found that compared with parental cells, NDRG2 expression is down-regulated in HER2-positive drug resistant breast cancer cells and up-regulated expression of NDRG2 can inhibit drug resistance of HER2-positive drug resistant breast cancer cells. Further studies showed that the loop of NDRG2/p53 can significantly increase levels of E3 ubiquitin ligase Siah1 to regulate HER2 protein degradation.In summary, we speculate that NDRG2 can inhibit the drug resistance of HER2-positive breast cancer and the reason is that the loop of NDRG2/p53 increases Siah1 expression to regulate HER2 protein degradation by ubiquitin pathway. This study is focused on the role and molecular mechanism of NDRG2 on reversing the drug resistance of HER2-positive breast cancer from the cell functions, the molecular mechanism and clinical significance. It is important to optimize anti-HER2 treatment strategy.

英文关键词： breast cancer;HER2;NDRG2;drug resistance;ubiquitin