miR-199a抑制卵巢癌干细胞耐药性的分子机制研究

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer deaths with a 5-year survival rate of only 15%. Recurrent disease associated with development of chemoresistance and metastasis is the major cause of mortality for patients with ovarian cancer. Current evidence from our lab suggests ovarian cancer stem cells (OCSCs) are the putative mediators of chemoresistance and metastasis, and might be the source of recurrence. Unfortunately, existing first-line chemotherapy fails in more than 80-90% of EOC patients with metastatic malignancies, since conventional agents are directed, predominantly, at rapidly proliferating tumor cells, not the ovarian cancer stem cells (OCSCs). Thus, there is a need to identify novel and more effective approaches to target OCSCs and therefore benefit ovarian cancer patients. Recently, we found microRNA-199a can sensitize OCSCs to Carboplatin, and investigated the mechanism of miR-199a inhibiting OCSCs' chemoresistance. We will use qPCR, WB,cell transfection, Doxcycline inducible miR-199a expression system to discover the molecular mechanism of miR-199a enhance the function of Carboplatin on OCSCs, and also will use biodegradable poly(lactic-co-glycolic acid) nanoparticles(PLGA-NP) as a carrier for miR-199a delivery to test if PLGA-NP-miR-199a can sensitize OCSCs to Carbo. This project plans to focus on investigating the molecular mechanism of role of miR-199a in this process mentioned above, and developing the potential translational stratigy using the mice tumor model. This project will significantly deep our understanding the role of miR-199a in OCSCs, and contribute to develop a novel cancer-stem-cell-target therapeutic approach in ovarian cancer.

卵巢上皮癌在妇科生殖系统癌症中死亡率排第一位。卵巢癌复发后通常伴随有化疗耐药与转移扩散是卵巢癌致死的主要原因，申请人研究结果显示，卵巢癌干细胞是卵巢癌复发、化疗耐药以及转移扩散的主要根源。当前一线化疗药物在80-90%的卵巢癌复发患者身上都是失败的，因为它们只是直接针对那些快速分裂增殖的普通卵巢癌细胞，还没有专门针对卵巢癌干细胞的临床药物。申请人首次用体外试验结果显示microRNA-199a能够降低卵巢癌干细胞的化疗抗性，并初步揭示其分子机制。本课题将应用受强力霉素诱导调控的miR-199a表达系统，qPCR，WB，真核转染等手段深入研究miR-199a抑制卵巢癌干细胞化疗耐药性的机制，用可生物降解多聚纳米颗粒包装miR-199a，尝试建立基于靶向针对卵巢癌干细胞的治疗新途径。该研究对进一步理解miR-199a调控卵巢癌干细胞各项生物学特性的作用机理，开发新的卵巢癌治疗药物都具重要意义。

卵巢上皮癌在妇科生殖系统癌症中死亡率排第一位。卵巢癌复发后通常伴随有化疗耐药与转移扩散是卵巢癌致死的主要原因,本课题组前期的研究结果显示,卵巢癌干细胞是卵巢癌复发、化疗耐药以及转移扩散的主要根源。当前一线化疗药物在80-90%的卵巢癌复发患者身上都是失败的,因为它们只是直接针对那些快速分裂增殖的普通卵巢癌细胞,还没有专门针对卵巢癌干细胞的临床药物。本课题组用体外试验结果显示 microRNA-199a 能够增强卡铂对卵巢癌干细胞的杀伤作用，起到化疗增敏的作用,应用受强力霉素诱导调控的 miR-199a 表达系统,qPCR,WB,真核转染等手段深入研究 miR-199a 抑制卵巢癌干细胞化疗耐药性的机制，初步揭示了miR-199a是通过抑制IKKbeta的表达，进而抑制卵巢癌干细胞的干性维持，使其失去了对化疗药物卡铂的抵抗作用,该研究对进一步理解 miR-199a 调控卵巢癌干细胞各项生物学特性的作用机理,开发新的卵巢癌治疗药物都具重要意义。