Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis
Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis
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DOI：
10.1016/j.canlet.2015.01.010
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发表时间：
2015-04-01
期刊：
影响因子：
9.7
通讯作者：
Kruyt, Frank A. E.
中科院分区：
文献类型：
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作者：
Joseph, Justin V.;Conroy, Siobhan;Kruyt, Frank A. E.
胶质母细胞瘤（GBM）是成人中最常见的脑肿瘤，据报道间充质GBM亚型是最恶性的，表现为严重的缺氧和坏死。在这里，我们研究了缺氧微环境在诱导间充质和侵袭性表型中的可能作用。非间充质SNB75和U87细胞暴露于缺氧诱导细胞形态发生强烈变化，并伴有侵袭能力增强和间充质标志物表达的获得。进一步的分析表明，缺氧和暴露于地高辛（一种已知能抑制HIF1/2表达的心糖苷）诱导HIF1 α和HIF2 α能够阻止缺氧诱导的间质转化。shrna介导的HIF1 α的敲低，而不是HIF2 α的敲低，阻止了这种转变，以及EMT转录因子ZEB1的敲低。我们通过发现GLUT1、ZEB1和间充质标记物YKL40在肿瘤缺氧区域共定位，为低氧诱导的GBM原发物质间充质转移提供了进一步的证据。总的来说，我们的研究结果确定了HIF1 α - zeb1信号轴，该信号轴以细胞系依赖的方式促进缺氧诱导的GBM间质转移和侵袭。2015爱思唯尔爱尔兰有限公司版权所有。
Glioblastoma (GBM) is the most common brain tumor in adults and the mesenchymal GBM subtype was reported to be the most malignant, presenting severe hypoxia and necrosis. Here, we investigated the possible role of a hypoxic microenvironment for inducing a mesenchymal and invasive phenotype. The exposure of non-mesenchymal SNB75 and U87 cells to hypoxia induced a strong change in cell morphology that was accompanied by enhanced invasive capacity and the acquisition of mesenchymal marker expression. Further analyses showed the induction of HIF1 alpha and HIF2 alpha by hypoxia and exposure to digoxin, a cardiac glycoside known to inhibit HIF1/2 expression, was able to prevent hypoxia-induced mesenchymal transition. ShRNA-mediated knockdown of HIF1 alpha, and not HIF2 alpha, prevented this transition, as well as the knockdown of the EMT transcription factor ZEB1. We provide further evidence for a hypoxia-induced mesenchymal shift in GBM primary material by showing co-localization of GLUT1, ZEB1 and the mesenchymal marker YKL40 in hypoxic regions of the tumor. Collectively, our results identify a HIF1 alpha-ZEB1 signaling axis that promotes hypoxia induced mesenchymal shift and invasion in GBM in a cell line dependent fashion. (C) 2015 Elsevier Ireland Ltd. All rights reserved.