洛伐他汀靶向乳腺癌干细胞抑制EMT和转移的作用及机制

项目名称： 洛伐他汀靶向乳腺癌干细胞抑制EMT和转移的作用及机制

项目编号： No.81472496

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： 邓锡云

作者单位： 湖南师范大学

项目金额： 70万元

中文摘要： 肿瘤干细胞是肿瘤耐药、转移和复发的根源。缺氧诱导因子HIF-1是肿瘤在缺氧条件下与干细胞表型获得密切相关的转录因子。我们研究发现，天然化合物洛伐他汀（LV）能够：1）抑制高度恶性的MDA-231乳腺癌细胞的增殖并诱导其凋亡；2）抑制来源于MDA-231的肿瘤干细胞的增殖和肿瘤球形成；3）下调MDA-231细胞中HIF-1alpha的蛋白水平并可逆转EMT和转移相关蛋白的表达。我们推想LV有可能通过降低HIF-1的活性抑制EMT表型和转移能力，因而可作为一种靶向乳腺癌干细胞的药物应用于乳腺癌治疗。本项目利用体外分子细胞模型、活体生物发光成像模型并结合临床乳腺癌标本，研究LV在体内外对乳腺癌干细胞特性特别是对EMT和转移的影响并探讨其分子机制，为将LV作为抗乳腺癌的天然药物推向临床奠定坚实的实验和理论基础。

中文关键词： C21_乳腺肿瘤；洛伐他汀；肿瘤干细胞；肿瘤转移

英文摘要： Cancer stem cells play a major role in drug resistance, metastasis and recurrence. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is closely related to the cancer stem cell phenotype under hypoxic conditions. Our preliminary studies have shown that the natural compound lovastatin could: 1) inhibit the proliferation and induce apoptosis in the highly malignant MDA-231 cells; 2) suppress the proliferation and tumorsphere formation of breast cancer stem cells derived from MDA-231 cells; 3) down-regulate the protein level of HIF-1alpha and the reverse the expression of epithelial-mesenchymal transition (EMT) and metastasis-related proteins. We hypothesize that lovastatin can inhibit the EMT phenotype and the metastatic potential through inhibition of HIF-1 activity and can be used as a drug to treat breast cancer through targeting cancer stem cells. This project is intended to study the effects of lovastatin on the biological properties of breast cancer stem cells especially on the EMT and metastasis and explore the molecular mechanisms involved, using in vitro molecular and cell culture models, in vivo bioluminescent imaging model, and breast cancer clinical samples. Implementation of this project will provide an important experimental and theoretical basis for pushing forward the clinical use of lovastatin as a natural anti-breast cancer drug.

英文关键词： Breast cancer;Lovastatin;Cancer stem cells;Cancer metastasis