PI3K/Nrf2信号通路协同调控乳腺癌EMT及侵袭转移的分子机制

项目名称： PI3K/Nrf2信号通路协同调控乳腺癌EMT及侵袭转移的分子机制

项目编号： No.81460399

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈丽艳

作者单位： 延边大学

项目金额： 47万元

中文摘要： 侵袭转移是导致乳腺癌预后不良的主要原因，EMT则是诱发肿瘤浸润和转移的早期重要事件。目前研究表明，PI3K/Akt和Nrf2/ARE通路与多种肿瘤的发生、转移和治疗密切相关，但两条通路协同调控肿瘤EMT及侵袭性的相关机制尚不清楚。项目组前期工作发现，Nrf2通路下游重要因子NQO1蛋白在乳腺癌患者肿瘤组织中的异常高表达与患者预后密切相关；PI3K信号通路特异性抑制剂BEZ235与NQO1特异性抑制剂Dicoumarol联合用药可协同抑制MCF-7乳腺癌细胞增殖，并对EGF诱导的细胞EMT改变具有抑制作用。因此，本项目拟通过细胞实验和裸鼠模型建立，在体内外检测PI3K/Akt通路与Nrf2/ARE/NQO1通路联合抑制对乳腺癌EMT及侵袭性的影响，分析PI3K/Nrf2通路协同调控乳腺癌EMT及侵袭的作用机制，为乳腺癌EMT发生提供新的分子解释，并为乳腺癌转移控制提供新靶点及靶向药物选择。

中文关键词： C21_乳腺肿瘤；PI3K；Nrf2；协同调控；上皮间质转化

英文摘要： Invasion and metastasis is the leading cause of death of most patients with breast cancer, which can be induced by Epithelial-Mesenchymal Transition (EMT) in its early stage. Recent studies demonstrated that, as two important signaling pathways, PI3K/Akt pathway and Nrf2/ARE pathway dysregulated in many cancers, including breast cancer. However, what role two pathways cross-talk plays in metastasis of breast cancer is poorly understood. In our previous studies, we found that NQO1, one of downstream gene of Nrf2 pathway, was overexpressed in breast cancer which was closely related with prognosis of patients. We also found that PI3K/mTOR inhibitor BEZ235 could reduce NQO1 protein expression and inverse EMT progress in breast cancer cell line MCF-7. Taken together, we plan to further investigate the effect of dual inhibition of the PI3K/Akt pathway and Nrf2/ARE/NQO1 pathway in breast cancer in vitro and in vivo, explore the mechanism of two pathways co-regulation on tumor EMT and metastasis. These will not only extend the theoretical basis of EMT regulation in breast cancer, but also provide new intervention targets for cancer treatment.

英文关键词： breast cancer;PI3K;Nrf2;co-regulation;EMT