子宫内膜再生细胞来源外泌体通过miR-125b对卵巢癌血管生成的调控作用及其机制的研究

Anti-angiogenesis is an important non-surgical treatment for ovarian cancer, but current therapies have shown only modest efficacy and need to be improved. Stem cell is applied in the research of angiogenesis regulation because of its powerful paracrine ability, and exsomes derived from the stem cells have un-comparable advantages. They can package and enrich the genetic information from the stem cells selectively and deliver them to the target sites, and moreover, avoid the side effects of cell transplantation. But will the stem cell-derived exosomes have therapeutic effect on the angiogenesis of ovarian cancer? In previous study, we found that exosomes derived from endometrial regenerative cells (ERC-exo), a group of cells isolated from menstrual blood representing stem cell features, could suppress ovarian tumor angiogenesis in vitro, which is probably mediated by miR-125b. However, what is the exact effect of ERC-exo on the angiogenesis of ovarian cancer, how does miR-125 work, and what are the down-stream targets are yet to be investigated. We are going to use research methods such as RNA-Seq and RNA interference, to prove the hypothesis that “ERC-exo regulate the angiogenesis of ovarian cancer via miR-125b”. This project will place theoretical basis for the study of the molecular mechanism how ERCs-exo play its role in tumor micro-environment, and therefore provide a potential approach to the anti-angiogenic therapy of ovarian cancer.

抗血管生成是卵巢癌的重要非手术治疗手段，然而现有药物作用较为局限，亟待优化。干细胞因其强大的外分泌功能而被应用于血管生成的干预性研究，而外泌体不仅能选择性包装、富集与递送来自干细胞的生物学信息，同时也规避了细胞移植的诸多问题。那么，干细胞源的外泌体是否能达到有效的抗卵巢癌血管生成作用？前期研究我们发现，月经血中子宫内膜再生细胞（具有干细胞特征）分泌的外泌体（ERC-exo）能明显抑制卵巢癌血管生成，且miR-125b或在这一过程中起关键作用。但ERC-exo对卵巢癌血管生成究竟作用如何，其携带的miR-125b如何实现调控作用，下游靶点又是什么，迄今尚无相关报道。本研究拟采用基因测序、RNA干扰等技术，证实“ERCs-exo通过miR-125b调控卵巢癌血管生成”这一推测，并阐明相关机制。这将为研究ERC-exo对肿瘤微环境的调控提供理论基础，并为卵巢癌抗血管生成治疗的优化提供新思路。

抗血管生成治疗是卵巢癌的重要非手术治疗手段，然而现有药物作用较为局限，尤其是获得性耐药的出现严重影响了治疗效果，因此亟待优化。近年来，干细胞因具有强大的外分泌功能而被应用于血管生成的干预性研究，而其分泌的外泌体不仅能选择性地包装、富集与递送干细胞的生物学信息，同时还能规避细胞移植的诸多问题。本研究聚焦干细胞来源外泌体对肿瘤血管生成的干预作用，在前期研究基础上，采用基因测序、蛋白质组学、RNA干扰、卵巢癌裸鼠模型等方法技术，从分子、细胞及体内水平，验证了提出的假说“ERCs-exo通过miR-125b调控卵巢癌血管生成”。在研究中，我们：（1）从月经血中分离获得了ERCs，并提取了外泌体、线粒体；（2）明确了ERCs对卵巢癌及其血管生成的作用；（3）证实了ERC-exo是ERCs抑制卵巢癌血管生成的主要功能成分；（4）明确了ERCs及ERC-exo中的miR-125b对卵巢癌血管生成的重要调控作用；（5）明确了miR-125b通过抑制促血管生成基因的转录因子E2F2，网格化地下调促血管生成基因，从而调控卵巢癌血管生成。证实了干细胞来源外泌体对肿瘤血管生成的调控作用。本研究从全新视角阐明了ERC-exo调控肿瘤微环境的分子机制，为进一步明确ERC-exo对肿瘤的治疗价值、探索抗血管生成治疗的新方法提供了新的思路，对于优化卵巢癌非手术治疗具有重大的现实意义和良好的应用价值。