外泌体中miR-25通过诱导血管渗透和血管形成调控结直肠癌转移前微环境形成的作用机制

Exosomes are one of the tumor derived factors inducing pre-metastatic niche formation in distant organs. Our previous study show that exosomal miR-25 derived from colorectal cancer cells promotes vascular permeability and angiogenesis both in vivo and vitro. Based on the bioinformatic analyses and preliminary experiments, we presume that uptake of exosomal miR-25 by vascular Endothelial Cells caused downregulation of KLF2 and KLF4, which lessens the expression of ZO-1,occludin,claudin5 and risens the expression of VEGFR2, leads to vascular leakiness and angiogenesis. This study will conform (1) miR-25 can be transferred from cancer cells to endothelial cells；(2)KLF2 and KLF4 are target gene of miR-25; (3)Exosomal miR-25 derived from colorectal cancer cells promotes vascular permeability and angiogenesis in vitro and induces pre-metastatic niche formation in vivo ; (4)Exosomal miR-25 derived from sera of patients with CRC could be used to evaluate the risk of CRC metastasis. This study aims to unveil a novel mechanism of pre-metastatic niche formation and provide novel miRNA targets and therapy strategy against CRC metastasis.

外泌体是肿瘤诱导远端器官形成转移前微环境的重要因素之一。前期工作中，我们发现癌细胞外泌体miR-25能促进体外血管渗透、血管形成及小鼠肝、肺血管通透性。根据生物信息学预测及预实验结果，我们提出假设：癌细胞外泌体miR-25被转移前微环境中血管内皮细胞摄取后，可抑制其靶基因KLF2和KLF4，进而下调紧密连接蛋白ZO-1、occludin、claudin5并促进VEGFR2表达，从而促进血管通透、血管生成及结直肠癌转移。本研究拟证实：（1）miR-25通过外泌体途径从结直肠癌细胞转运至血管内皮细胞；（2）KLF2和KLF4是miR-25的功能靶基因；（3）癌细胞外泌体中miR-25通过KLF2和KLF4调控血管通透、血管生成及结直肠癌转移；（4）评估血清外泌体miR-25在结直肠癌患者转移预测中潜在应用价值。旨在揭示转移前微环境形成的新机制,为临床预测、控制肿瘤转移提供新的靶点和治疗策略。

肿瘤来源的外泌体是癌症诱导远端器官转移前微环境形成的主要驱动因子，但其机制仍不清楚。我们的研究表明miR-25-3p是一个促进结直肠癌转移相关miRNA，它可以通过外泌体从结直肠癌细胞转运至血管内皮细胞。外泌体miR-25-3p通过靶向KLF2和KLF4调节内皮细胞中VEGFR2、ZO-1、occludin和Claudin5的表达，从而促进血管渗透和血管生成。此外，结直肠癌细胞外泌体中miR-25-3p能诱导远端器官血管渗透，并促进CRC远处转移。此外，与不伴转移转移的患者相比，伴转移的结直肠癌患者血清外泌体中miR-25-3p的表达水平明显升高。我们的工作表明，外泌体miR-25-3p参与了转移前微环境的形成，可作为结直肠癌转移的风险评估标志物。