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首页> 外文期刊>Cytokine >Int6/eIF3e silenced HIF2α stabilization enhances migration and tube formation of HUVECs via IL-6 and IL-8 signaling
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Int6/eIF3e silenced HIF2α stabilization enhances migration and tube formation of HUVECs via IL-6 and IL-8 signaling

机译：Int6 / eIF3e沉默的HIF2α稳定通过IL-6和IL-8信号传导增强HUVEC的迁移和管形成

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We previously identified the tumor suppressor INT6/eIF3e as a novel down regulator of HIF2α. Small interfering RNA targeting Int6 (siRNA-Int6) in HeLa cells led to normoxic stabilization of HIF2α, with concomitant transcription of angiogenic factors, including angiopoietin, basic fibroblast growth factor, and vascular endothelial growth factor. Here we used HIF2α normoxic up-regulation via Int6 silencing to investigate the role of HIF2α in endothelial cells. As a result Int6 silencing in human umbilical vein endothelial cells (HUVECs) and in human aortic endothelial cells (HAECs) led to robust enhanced cord formation and the medium supernatant of Int6 silenced HUVECs enhanced migration of untreated HUVECs, indicating a HIF2α triggered secretory signaling. Within the responsible genes were the cytokines interleukin-6 (IL-6) and IL-8 and not unlike in HeLa cells vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and epidermal growth factor (EGF). In addition application of IL-6 and IL-8 antibodies to the medium of Int6 silenced HUVECs could reverse the enhanced migration effect and also abrogated their tube formation. Finally, a CHIP assay analysis confirmed hypoxia-responsive elements (HREs) in the IL-6 and IL-8 promoters. Our results demonstrate that expression of both IL-6 and IL-8 is regulated by HIF2α and we suggest that IL-6 and IL-8 are HIF2α controlled cytokines for angiogenesis particularly in endothelial cells.
机译：我们先前将肿瘤抑制基因INT6 / eIF3e确定为HIF2α的新型下调因子。 HeLa细胞中靶向Int6的小干扰RNA（siRNA-Int6）导致HIF2α的常氧稳定，并伴随血管生成因子（包括血管生成素，碱性成纤维细胞生长因子和血管内皮生长因子）的转录。在这里，我们使用了通过Int6沉默的HIF2α常氧上调来研究HIF2α在内皮细胞中的作用。结果，人脐静脉内皮细胞（HUVEC）和人主动脉内皮细胞（HAEC）中的Int6沉默导致牢固的脐带形成增强，而Int6沉默的HUVEC的培养基上清液增强了未经处理的HUVEC的迁移，表明HIF2α触发了分泌信号传导。在负责任的基因内是细胞因子白介素6（IL-6）和IL-8，与HeLa细胞中的血管内皮生长因子（VEGF），肝细胞生长因子（HGF）和表皮生长因子（EGF）相似。此外，在Int6沉默的HUVEC培养基上应用IL-6和IL-8抗体可以逆转增强的迁移作用，也可以消除其管形成。最后，CHIP分析证实了IL-6和IL-8启动子中的缺氧反应元件（HRE）。我们的结果表明，IL-6和IL-8的表达均受HIF2α调节，我们建议IL-6和IL-8是HIF2α调控的血管生成细胞因子，特别是在内皮细胞中。

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