Extracellular Vesicles Containing MicroRNA-92a-3p Facilitate Partial Endothelial-Mesenchymal Transition and Angiogenesis in Endothelial Cells
Extracellular Vesicles Containing MicroRNA-92a-3p Facilitate Partial Endothelial-Mesenchymal Transition and Angiogenesis in Endothelial Cells
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DOI：
10.3390/ijms20184406
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发表时间：
2019-09-02
影响因子：
5.6
通讯作者：
Senda, Takao
中科院分区：
文献类型：
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作者：
Yamada, Nami O.;Heishima, Kazuki;Senda, Takao
细胞外囊泡（EVs）是用于原始细胞间通讯的纳米级膜性囊泡。我们先前报道结肠癌来源的细胞外囊泡含有丰富的miR - 92a - 3p，并具有促血管生成功能。我们先前已确定Dickkopf - 3（Dkk - 3）是miR - 92a - 3p的直接靶标；然而，miR - 92a - 3p的促血管生成功能不能仅仅归因于Dkk - 3的下调。因此，miR - 92a - 3p发挥促血管生成作用的完整分子机制仍不清楚。在此，我们全面分析了内皮细胞中miR - 92a - 3p异位表达所影响的基因集，以阐明细胞外囊泡诱导血管生成的潜在过程。我们发现miR - 92a - 3p的异位表达上调了内皮细胞中细胞周期和有丝分裂相关基因的表达，并下调了黏附相关基因的表达。我们还确定了miR - 92a - 3p的一个新靶基因，claudin - 11。Claudin - 11属于claudin基因家族，该家族编码在紧密连接（TJs）处表达的关键成分。紧密连接的破坏以及伴随的claudin表达缺失是上皮 - 间质转化过程中的一个重要事件。我们的研究结果揭示了一种新的细胞外囊泡介导的肿瘤血管生成机制，即通过诱导内皮细胞发生部分内皮 - 间质转化。
Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.