ADAM10对乳腺癌中PrPc核内转运、多药耐药及侵袭转移的调控研究

项目名称： ADAM10对乳腺癌中PrPc核内转运、多药耐药及侵袭转移的调控研究

项目编号： No.81502273

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： 程园园

作者单位： 复旦大学

项目金额： 18万元

中文摘要： 肿瘤多药耐药和侵袭转移是引起乳腺癌病人死亡的两大原因，且肿瘤细胞对化疗药物产生耐药的同时，其侵袭转移能力也增强，但相关分子机制尚未完全阐明。申请者前期研究发现与耐药及侵袭转移相关的跨膜糖蛋白PrPc，在乳腺癌细胞膜表达的同时,在细胞核中也有表达。文献报道PrPc细胞核内发挥生物学功能的结构域为其N末端水解蛋白，而ADAM10在PrPc蛋白水解过程中起调控作用，我们的预实验发现ADAM10在耐药乳腺癌细胞中高表达。本课题旨在乳腺癌敏感细胞株及耐药细胞株中，通过激光共聚焦显微镜、透射电镜、Western Blot、基因转染等方法检测PrPc在乳腺癌细胞核内发挥生物学功能的结构域，ADAM10对其水解、细胞核内转运的调控；体外及体内实验探索ADAM10对乳腺癌耐药、侵袭转移能力的影响及其机制。本研究将为深入揭示肿瘤耐药与侵袭转移相关机制提供重要的理论和实验依据，为乳腺癌的临床治疗提供新策略。

中文关键词： 乳腺肿瘤；ADAM10；PrPc；多药耐药；侵袭转移

英文摘要： Multidrug resistance (MDR)and invasion/metastasis are two important factors leading to death in breast cancer patients. The tumor invasive/metastatic ability is strengthened accompanied by MDR. However,the underlying mechanisms have not been fully elucidated. Our previous study showed that the transmembrane glycosidoprotein PrPc related to MDR and invasion/metastasis is detected both in cytomembrane and in nucleus in breast cancer. It is demonstrated that the N-terminal fragment of PrPc plays important roles in nucleus, and the endoproteolytic cleavage of PrPc is regulated by ADAM10. Our pre-experiments found that ADAM10 is overexpressed in MDR breast cancer cells. Here, we establish in drug-sensitive and drug-resistant breast cancer cell lines which domain of PrPc plays roles in nuclues, and the regulation of endoproteolytic cleavage and nuclear trafficking of PrPc by ADAM10. We also demonstrate in vitro and in vivo ADAM10 mediates MDR and invasion/metastasis in breast cancer. Our findings will not only further discover the mechanism underlying the functional linkage between drug resistance and tumor metastasis, but also provide new strategies to guide the clinical chemotherapy in breast cancer patients.

英文关键词： breast tumor;ADAM10;PrPc;multidrug resistance;invasion/metastasis