分子伴侣自噬（CMA）在乳腺癌转移中的作用及机制研究

项目名称： 分子伴侣自噬（CMA）在乳腺癌转移中的作用及机制研究

项目编号： No.81472481

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： 李淑慧

作者单位： 中国人民解放军第三军医大学

项目金额： 72万元

中文摘要： 乳腺癌是严重威胁妇女健康的重大疾病,转移是乳腺癌患者的主要死因和影响救治率进一步提高的关键因素，深入阐明其中的具体机制对于提高乳腺癌的防治水平具有重要意义。我们前期通过组织芯片，发现CMA途径的关键蛋白LAMP2A异常高表达于乳腺癌上皮组织，且与乳腺癌的分级呈正相关；通过Transwell侵袭和裸鼠接种试验，发现CMA能促进乳腺癌细胞转移；基因芯片结果显示，LAMP2A表达下调后，与肿瘤转移密切相关的SphK1/S1P信号通路相关基因表达发生改变。由此我们推测CMA可能通过SphK1/S1P信号通路进而促进乳腺癌细胞转移。本项目拟在上述工作基础上，通过小鼠乳腺癌肺转移等体内外转移模型及临床样本，进一步明确CMA在乳腺癌转移中的作用，并探讨CMA调节SphK1/S1P通路促进乳腺癌转移的可能分子机制。旨在为从CMA角度解释乳腺癌转移新机制积累资料，并为临床乳腺癌诊治提供可能靶点和有益线索。

中文关键词： C21_乳腺肿瘤；分子伴侣自噬；转移

英文摘要： Breast cancer is a major gynecological malignancy that threatens the health of females, with tumor metastasis being one of the main cause of death and obstacles in raising cure rate. We previously discovered by tissue chip analysis that the key protein lysosomal-associated membrane protein 2A (LAMP2A) in the chaperone-mediated autophagy(CMA) pathway was abnormally over expressed in the epithelial tissue of breast cancer, and the level of LAMP2A expression has a positive correlation with breast cancer grading. Meanwhile, through the tests of transwell invasion and subcutaneus innoculation of BALB/c nude mice with different cell strains of diverse LAMP2A expression levels, we found that CMA could promote the metastasis of breast cancer cells; Gene chip analysis after downregulation of LAMP2A revealed the gene expression level varied in the sphingosine kinase Sphk1/S1Psignaling pathway closely related with tumor metastasis. Based upon previous work, this project aims to further elucidate the role of CMA in the metastasis of breast cancer and to investigate the possible molecular mechanism in which CMA promotes breast cancer metastasis by regulation of the Sphk1/S1P signaling pathway with in vitro and in vivo cell and animal models and clinical samples. This project will benefit improving our knowledge in the field of breast cancer metastasis from a CMA perspective, providing useful clues and possible therapeutic targets for clinical diagnosis and treatment of the disease.

英文关键词： breast cancer;chaperone mediated autophagy;metastasis