新型生长抑制因子BDGI诱导的细胞自噬在乳腺癌发生中的作用及其机制研究

项目名称： 新型生长抑制因子BDGI诱导的细胞自噬在乳腺癌发生中的作用及其机制研究

项目编号： No.31471297

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 夏大静

作者单位： 浙江大学

项目金额： 85万元

中文摘要： 生长抑制因子具有潜在的抗肿瘤作用，骨髓基质细胞来源的生长抑制因子（BDGI）是本课题组克隆的新型生长抑制因子，可通过诱导凋亡和细胞周期阻滞抑制乳腺癌细胞的生长，但其确切机制尚不明了。我们最新研究结果显示BDGI能诱导乳腺癌细胞的自噬，且该自噬可抵抗饥饿导致的细胞死亡，BDGI诱导的自噬是通过和JNK与Bcl-2相关的mTOR非依赖途径。本项目拟在此基础上，建立过表达及knockdown BDGI的乳腺癌稳定细胞株，进一步研究BDGI对细胞自噬的诱导作用及自噬在乳腺癌发生中所扮演的角色，阐明BDGI诱导自噬的信号转导途径和相关分子机制，同时建立裸鼠乳腺癌模型（同鼠双侧肿瘤对照模型）、收集临床标本，通过内、体外实验明确BDGI的表达水平、自噬程度与肿瘤发生发展间的关系。该项目的完成有望揭示BDGI的生理、病理功能以及BDGI抗肿瘤的确切分子机制，为开发新的抗肿瘤药物和寻找治疗靶分子提供思路。

中文关键词： 基质细胞来源的生长抑制因子；自噬；乳腺癌；凋亡

英文摘要： Growth inhibitors are well known to play an important role in tumor suppression. Bone marrow stromal cell-derived growth inhibitor (BDGI) is a growth inhibitory factor originally identified and cloned by our group (GenBank #AY037158), with known functions in suppressing human breast cancer cell growth via induction of cycle arrest and apoptosis. Our preliminary data indicate that BDGI is able to promote autophagy and such inducible autophagy serves as a pro-survival mechanism in protection of cancer cells against cell death. Moreover, we also have evidence indicating that BDGI-mediated autophagy is regulated by a JNK-dependent pathway independent of mechanistic target of rapamycin (mTOR). In this proposed study, we aim to systematically study the effect of BDGI on autophagy by modulation of BDGI level in human breast cancer cells (with over expressed and knockdown BDGI stable cells) and to understand the biological function of such autophagy in breast cancer cells, using both cell culture and nude mice xenograft model. Moreover, we will investigate the molecular mechanisms underlying BDGI-mediated autophagy by focusing on the roles of JNK and Bcl-2. Finally, we will compare the BDGI expression level in human breast cancer tissues and adjacent normal tissues and establish the association with the autophagic markers and tumor development stages. Taken together, results from this study will provide novel evidence in understanding the important function of BDGI in tumor suppression and support the development of novel anti-cancer approaches by targeting BDGI-mediated autophagic process.

英文关键词： BDGI;autophagy;breast cancer;apoptosis