EIF4A3诱导的卵巢癌细胞源外泌体circRNA circ_HIPK3调控miR-375/YAP1通路促进肿瘤血管生成的机制研究

肿瘤微环境中肿瘤细胞与血管内皮细胞间通讯参与卵巢癌转移及血管生成，但其细胞间机制并未完全阐明。肿瘤来源外泌体circRNAs可以被受体细胞吸收，参与受体细胞功能调节，发挥细胞间通讯作用。RNA结合蛋白EIF4A3可参与circRNA的生成，转录及外泌体细胞外运输。预实验示：低氧上调卵巢癌细胞EIF4A3表达及外泌体circ_HIPK3，卵巢癌源外泌体可促进HUVEC增殖及迁移；miR-375可调控YAP1参与血管生成。circ_HIPK3在卵巢癌细胞及血管内皮细胞均有表达。结合前期基础及生物信息学分析，我们提出以下假说：低氧-EIF4A3↑-卵巢癌细胞外泌体circ_HIPK3↑-血管内皮细胞circ_HIPK3↑-海绵吸附miR-375↓-YAP1↑-促进血管生成。本项目聚焦探索外泌体circRNA在肿瘤细胞与血管内皮细胞间的沟通机制，为设计靶向上述通路的抗血管生成药提供新思路。

The cross talk between tumor cells and vascular endothelial cells in the tumor microenvironment is involved in ovarian cancer tumorigenesis, metastasis and angiogenesis, but the intercellular mechanism is still not clearly understood. More and more studies suggest that tumor-derived exosome circRNAs can be absorbed by recipient cells and involved in the regulation of recipient cell functions and play an intercellular communication role as a “shuttle bus”. The RNA-binding protein EIF4A3 can participate in the generation, transcription, and transport of exo-circRNAs to the outside of cells. Pre-experiments show that hypoxia up-regulates the expression of EIF4A3 in ovarian cancer cells and increases the expression of exosome circ_HIPK3. Exosomes absorbed by vascular endothelial cells can promote HUVEC cell proliferation and migration; miR-375 inhibition upregulate YAP1 and DSCR1-1L and promote angiogenesis. Circ_HIPK3 is proved to be expressed in both ovarian cancer cells and vascular endothelial cells. Whether ovarian cancer-derived exosome circ_HIPK3 can regulate YAP1 to participate in ovarian tumor angiogenesis through the ceRNA mechanism is very interesting. Based on the research basis and bioinformatics analysis, the following hypothesis is proposed: hypoxia up-regulates the expression of EIF4A3, which promotes the increase of exosome circ_HIPK3 in ovarian cancer cells； circ_HIPK3 is upregulated after exosomes entering in vascular endothelial cells, which promoted tumor angiogenesis as miR-375 “sponge” and consequently upregulate YAP1 and DSCR1-1L. We hope to further understand the cross-talk between tumor cells and vascular endothelial cells in the tumor microenvironment through this project, and provide new ideas for the design of anti-angiogenesis drugs targeting the EIF4A3 / circ_HIPK3 / miR-375 / YAP1 / DSCR1-1L pathway.