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. Implications: Overall, our data clarify the diagnostic and prognostic value of tumor-derived exosome-mediated miR-182-5p and reveal the distinctive cross-talk between tumor cells and human umbilical vein endothelial cells mediated by tumor-derived exosomes that modulate tumor vasculature.

中文翻译：

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缺氧癌症分泌的外泌体 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

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。肿瘤细胞释放的外泌体含有参与癌症和基质细胞相互作用的核酸、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，缺氧通过源自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细胞产生更多的外泌体，并且在缺氧条件下GBM细胞的外泌体中miR-182-5p显着上调。外泌体 miR-182-5p 直接抑制其靶标 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-182-5p 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。敲除 miR-182-5p 可减少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-182-5p 水平升高，其表达水平与预后呈负相关。影响：总体而言，