Solid tumor microenvironments are often subjected to various levels of hypoxia. Although regulation of gene expression has been examined extensively, most studies have focused on prolonged hypoxia. The tumor microenvironment, however, experiences waves of hypoxia and reoxygenation that stimulate the expression of pro-angiogenic factors that promote blood vessel formation. In this study, we examined human umbilical vascular endothelial cells (HUVECs) under waves of intermittent (cyclic) hypoxia to determine how this process compares to prolonged hypoxia, and more importantly, how this influences the microRNA profiles that potentially affect the posttranscriptional regulation of angiogenic genes. The rationale for these studies is that cancer cells subjected to cyclic hypoxia appear to have increased metastatic potential and endothelial cells exhibit a higher radiation resistance and greater migration potential. This indicates that gene regulatory networks in cyclic hypoxia may be different from prolonged hypoxia. Here we examined the consequences of cyclic hypoxia on miRNA gene expression and how these changes in miRNA expression influence angiogenesis. Using Next Generation Sequencing, our results demonstrate that cyclic hypoxia has very different effects on the miRNA networks compared to prolonged hypoxia, and that the in silico predicted effects on the certain mRNA target genes are more similar than might be expected. More importantly, these studies indicate that identifying potential miRNAs (including hsa-miR-19a-5p) as therapeutic targets for inhibiting angiogenesis and tumor progression will require this type of physiologically relevant analysis.

实体瘤微环境经常遭受各种程度的缺氧。尽管已经广泛检查了基因表达的调节，但是大多数研究都集中在长时间缺氧上。然而，肿瘤微环境经历了缺氧和复氧的浪潮，刺激了促进血管形成的促血管生成因子的表达。在这项研究中，我们检查了间歇性（循环）缺氧波下的人脐带血管内皮细胞（HUVEC），以确定该过程与长时间缺氧的比较，更重要的是，这如何影响可能影响血管生成后转录调控的microRNA谱基因。这些研究的基本原理是，遭受循环性缺氧的癌细胞似乎具有更高的转移潜能，而内皮细胞则具有更高的抗辐射能力和更大的迁移潜能。这表明循环性缺氧中的基因调控网络可能与长期缺氧不同。在这里，我们检查了循环缺氧对miRNA基因表达的影响，以及这些miRNA表达的变化如何影响血管生成。使用下一代测序，我们的结果表明，与长时间缺氧相比，循环性缺氧对miRNA网络的影响非常不同，并且 在这里，我们检查了循环缺氧对miRNA基因表达的影响，以及这些miRNA表达的变化如何影响血管生成。使用下一代测序，我们的结果表明，与长时间缺氧相比，循环性缺氧对miRNA网络的影响非常不同，并且 在这里，我们检查了循环缺氧对miRNA基因表达的影响，以及这些miRNA表达的变化如何影响血管生成。使用下一代测序，我们的结果表明，与长时间缺氧相比，循环性缺氧对miRNA网络的影响非常不同，并且在计算机上，预测对某些mRNA靶基因的作用比预期的更为相似。更重要的是，这些研究表明，鉴定潜在的miRNA（包括hsa-miR-19a-5p）作为抑制血管生成和肿瘤进展的治疗靶标将需要这种类型的生理相关分析。