Hypoxic Cancer-Secreted Exosomal miR-182-5p Promotes Glioblastoma Angiogenesis by Targeting Kruppel-like Factor 2 and 4 A
Hypoxic Cancer-Secreted Exosomal miR-182-5p Promotes Glioblastoma Angiogenesis by Targeting Kruppel-like Factor 2 and 4 A
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缺氧的癌症分泌的外泌体 miR-182-5p 通过靶向 Kruppel 样因子 2 和 4 促进胶质母细胞瘤血管生成
DOI：
10.1158/1541-7786.mcr-19-0725
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发表时间：
2020-08-01
影响因子：
5.2
通讯作者：
Xiong, Nanxiang
中科院分区：
文献类型：
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作者：
Li, Junjun;Yuan, Hongliang;Xiong, Nanxiang
胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤，具有复杂的分子特征。缺氧在肿瘤进展和肿瘤微环境（TME）中起着关键作用。由肿瘤细胞释放的外泌体含有参与癌症和基质细胞之间相互作用的信息核酸、蛋白质和脂质，从而导致TME重塑。越来越多的证据表明，外泌体在细胞间通讯中起着关键作用。然而，低氧通过来源于肿瘤细胞的外泌体影响肿瘤血管生成的机制在很大程度上仍然未知。在我们的研究中，我们发现，与常氧条件下的亲本细胞相比，GBM细胞产生更多的exosomes，并且在低氧条件下，miR-182- 5 p在GBM细胞的exosomes中显著上调。外泌体miR-182- 5 p直接抑制其靶点Kruppel样因子2和4，导致VEGFR的积累，从而促进肿瘤血管生成。此外，外泌体介导的miR-182- 5 p还抑制紧密连接相关蛋白（如ZO-1、occludin和claudin-5），从而增强血管通透性和肿瘤跨内皮迁移。miR-182- 5 p的敲低降低了血管生成和肿瘤增殖。有趣的是，我们发现患者血清和脑脊液样本中循环miR-182- 5 p水平升高，其表达水平与预后呈负相关。
Glioblastoma (GBM) is the most lethal primary brain tumor and has a complex molecular profile. Hypoxia plays a critical role during tumor progression and in the tumor microenvironment (TME). Exosomes released by tumor cells contain informative nucleic acids, proteins, and lipids involved in the interaction between cancer and stromal cells, thus leading to TME remodeling. Accumulating evidence indicates that exosomes play a pivotal role in cell-to-cell communication. However, the mechanism by which hypoxia affects tumor angiogenesis via exosomes derived from tumor cells remains largely unknown. In our study, we found that, compared with the parental cells under normoxic conditions, the GBM cells produced more exosomes, and miR-182-5p was significantly upregulated in the exosomes from GBM cells under hypoxic conditions. Exosomal miR-182-5p directly suppressed its targets Kruppel-like factor 2 and 4, leading to the accumulation of VEGFR, thus promoting tumor angiogenesis. Furthermore, exosome-mediated miR-182-5p also inhibited tight junction-related proteins (such as ZO-1, occludin, and claudin-5), thus enhancing vascular permeability and tumor transendothelial migration. Knockdown of miR-182-5p reduced angiogenesis and tumor proliferation. Interestingly, we found elevated levels circulating miR-182-5p in patient blood serum and cerebrospinal fluid samples, and its expression level was inversely related to the prognosis.