VISA-miR-34a高效纳米系统靶向杀灭乳腺癌干细胞的作用及机制研究

乳腺癌干细胞(BCSCs)与乳腺癌的发生、发展、耐药、转移和复发等有密切联系，但目前尚无有效的治疗方法。靶向杀灭乳腺癌干细胞是根治乳腺癌的关键之一。基因治疗的靶向输送是其治疗的瓶颈。特异性启动子介导的纳米颗粒是靶向输送的有效方法。申请者在前期研究中发现miR-34a在乳腺癌和BCSCs中低表达，合成的miR-34a可有效地抑制乳腺癌和BCSCs。本项目应用申请者研发的整合性放大系统（VISA系统,已获美国发明专利）和纳米颗粒技术（已申请中国发明专利），结合乳腺癌和BCSCs特异性人端粒酶逆转录酶启动子（hTERT）和miR-34a,建立高效高特异性的hTERT-VISA-miR-34a纳米靶向杀灭系统，高效表达miR-34a,靶向根除乳腺癌及其干细胞,研究其在BCSCs中可能的新靶基因和信号通路，以明确hTERT-VISA-miR-34a杀灭BCSCs机制，为高效靶向治疗提供坚实的基础。

Breast cancer stem cells are closely related to the tumorigenesis, development, metastasis,drug resistance and recurrence of breast cancer；however, by now no effective therapies are avaliable for BCSCs. Targeted therapy BCSCs is the one of the keys to cure breast cancer. The bottleneck of the gene thearpy is the targeted delivery. In the previous study, the applicants has found that the miR-34a downexpression in breast cancer, especially in BCSCs, and synthesis miR-34a mimics can effectively inhibit breast cancer and BCSCs.The project applied an integrated amplification system (VISA system, the applicant developed, has been a U.S. patent) and nanoparticles (has applied for invention patents in China), combined with breast cancer, and BCSCs specific human telomerase reverse transcriptase promoter (hTERT) and tumor suppressor miR-34a, to establishment of efficient high specificity of hTERT-VISA-miR-34a nanoparticles targeted system, efficient expression of miR-34a for targeting eradication of breast cancer stem cells. In addition, We aim to predict the moleculars which regulate miR-34a and clear the mechanism of the effect of miR-34a in breast cancer stem cells. This project will provide a solid fundation for breast cancer stem cells efficient targeted therapy.