Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2.
Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2.
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胶质瘤细胞通过释放含有长非编码RNA CCAT2的外泌体来增强血管生成并抑制内皮细胞凋亡
DOI：
10.3892/or.2017.5742
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发表时间：
2017-08
期刊：
影响因子：
4.2
通讯作者：
Xu GH
中科院分区：
文献类型：
--
作者：
Lang HL;Hu GW;Zhang B;Kuang W;Chen Y;Wu L;Xu GH
血管生成是胶质瘤进展的关键事件。外泌体作为细胞外信号细胞器，调节肿瘤微环境，促进血管生成和肿瘤进展。我们以前证明，长基因间非编码RNA CCAT 2（linc-CCAT 2）在胶质瘤组织中过表达，并发挥促进胶质瘤进展的作用。因此，本研究旨在探讨胶质瘤细胞影响血管生成的潜在机制。首先，采用qRT-PCR检测linc-CCAT 2在4种胶质瘤细胞系和293 T细胞中的表达水平，结果显示U87-MG细胞中linc-CCAT 2的表达水平最高。随后，在体外和体内评价了来源于阴性对照shRNA处理的U87-MG细胞（ncU 87-Exo）和linc-CCAT 2 shRNA处理的U87-MG细胞（shU 87-Exo）的外泌体的促血管生成功能。我们发现，ncU 87-Exo，这是丰富的linc-CCAT 2，可以采取由HUVECs。ncU 87-Exo可提高HUVEC中linc-CCAT 2的表达水平，促进HUVEC迁移、增殖、体外管状结构形成和体内小动脉形成，并抑制缺氧诱导的HUVEC凋亡。进一步的机制研究表明，ncU 87-Exo可上调HUVECs中VEGFA和TGFβ的表达，促进Bcl-2的表达，抑制Bax和caspase-3的表达。最后，功能获得/丧失研究表明，linc-CCAT 2在HUVECs中的过表达激活VEGFA和TGFβ，促进血管生成，促进Bcl-2表达，抑制Bax和caspase-3表达，从而减少凋亡。linc-CCAT 2的下调显示了相反的效果。因此，我们的研究结果揭示了一种新的外泌体介导的机制，通过这种机制，胶质瘤细胞可以通过外泌体将linc-CCAT 2转移到内皮细胞来促进血管生成。此外，我们建议外泌体和linc-CCAT 2是胶质瘤中假定的治疗靶点。
Angiogenesis is a key event in the progression of gliomas. Exosomes, as signaling extracellular organelles, modulate the tumor microenvironment and promote angiogenesis and tumor progression. We previously demonstrated that long intergenic non-coding RNA CCAT2 (linc-CCAT2) was overexpressed in glioma tissues and functioned to promote glioma progression. Therefore, this study aimed to explore an underlying mechanism of glioma cell-affected angiogenesis. First, qRT-PCR was used to determine the expression level of linc-CCAT2 in 4 glioma cell lines and 293T cells, and the results revealed that the U87-MG cells exhibited the highest expression level. Subsequently, the pro-angiogenesis function of exosomes that were derived from negative control shRNA-treated U87-MG cells (ncU87-Exo) and linc-CCAT2 shRNA-treated U87-MG cells (shU87-Exo) was evaluated in vitro and in vivo. We found that ncU87-Exo, which was enriched in linc-CCAT2, could be taken up by HUVECs. ncU87-Exo improved the linc-CCAT2 expression level in HUVECs and more strongly promoted HUVEC migration, proliferation, tubular-like structure formation in vitro and arteriole formation in vivo as well as inhibited HUVEC apoptosis induced by hypoxia. Further mechanistic studies revealed that ncU87-Exo could upregulate VEGFA and TGFβ expression in HUVECs as well as promote Bcl-2 expression and inhibit Bax and caspase-3 expression. Finally, gain-/loss-of-function studies revealed that the overexpression of linc-CCAT2 in HUVECs activated VEGFA and TGFβ, promoted angiogenesis, promoted Bcl-2 expression and inhibited Bax and caspase-3 expression, thus decreasing apoptosis. Downregulation of linc-CCAT2 revealed the opposite effect. Thus, our results revealed a new exosome-mediated mechanism by which glioma cells could promote angiogenesis through the transfer of linc-CCAT2 by exosomes to endothelial cells. Moreover, we suggest that exosomes and linc-CCAT2 are putative therapeutic targets in glioma.
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