miR-199a抑制卵巢上皮癌干细胞血管分化潜能的分子机制研究

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer deaths. The process of angiogenesis is indispensable for the process of tumor progression in these cases and contributes to the aggressive nature of the disease. Current evidence from our lab suggests ovarian cancer stem cells (OCSCs) are the putative mediators of tumor vasculorization,chemoresistance and metastasis, and might be the source of recurrence. Unfortunately, existing first-line chemotherapy failed 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, it is very eager to identify novel and more effective approaches to target OCSCs and therefore to benefit ovarian cancer patients. Recently, we found microRNA-199a can inhibit OCSCs’ differentiation to vessel, and we also investigated the mechanism of miR-199a inhibition function. We will use qPCR, WB,cell transfection, Doxcycline inducible miR-199a expression system to discover the molecular mechanism of miR-199a inhibiting OCSCs differentiation potential to tumor vascular progenitors , 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 enhance the inhibition role of the VEGF inhibitor(Avastion) on Tumor vascularization. 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 deepen our understanding of the role of miR-199a in OCSCs, and contribute to develop a novel cancer-stem-cell-target therapeutic approach for EOC patients.

卵巢上皮癌在妇科生殖系统癌症中死亡率排第一位。肿瘤血管生成是卵巢癌发展恶化过程中一个不可忽视的环节。申请人研究结果显示，卵巢癌干细胞是肿瘤血管生成、癌症复发、化疗耐药以及转移扩散的主要根源。目前一线化疗药物在80-90%的卵巢癌复发患者身上都是失败的，因为它们是直接针对那些快速分裂增殖的普通卵巢癌细胞，目前还没有专门针对卵巢癌干细胞的临床药物。申请人首次发现microRNA-199a能够抑制卵巢癌干细胞的血管分化潜能，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抑制卵巢癌干细胞血管分化潜能的机制，用可生物降解的多聚纳米颗粒包装miR-199a，尝试建立基于靶向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及开发新的卵巢癌治疗药物都具有重要意义。

卵巢癌在妇科生殖系统相关癌症中死亡率排第一位，在女性癌症中死亡率排第四位，5年存活率仅有15％。卵巢上皮癌是卵巢癌中最主要的一类，其复发后通常伴随有化疗耐药与转移扩散，这两者是卵巢上皮癌致死的主要原因。现存的一线化疗药物，以5年存活率为判定指标，在80-90%的卵巢上皮癌复发患者身上都是失败的， 是因为我们对卵巢癌的转移机制与耐药机制仍不是很清楚。.本课题的研究主要获得两项成果，1）miR-199a通过抑制IKKbeta进而抑制卵巢癌干细胞的血管分化潜能，其上游基因TWIST1的功能受到CBX7的抑制，进而使卵巢癌细胞发生间质上皮转化（MET），本研究成果最近刚被Oncogene接受； 2）Slug基因通过抑制miR-222的转录间接促进PDCD10基因的表达，进而促进卵巢癌细胞上皮间质转化（EMT），并促进卵巢癌的转移，这部分成果刚被Theranostics杂志接受。.通过本课题的研究，将有助于进一步阐明卵巢癌转移机制，具有潜在的临床应用价值。