JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation
JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation
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DOI：
10.1158/1541-7786.mcr-10-0508
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发表时间：
2011-05-01
影响因子：
5.2
通讯作者：
Axelson, Hakan
中科院分区：
文献类型：
--
作者：
Pietras, Alexander;von Stedingk, Kristoffer;Axelson, Hakan
一些研究已经揭示了实体瘤中缺氧和Notch激活之间的联系。虽然大多数报道都集中在Notch 1受体（icN 1）的细胞内结构域的稳定与HIF蛋白的直接相互作用，很少有人注意到Notch配体在缺氧过程中的调节。在这里，我们表明，Notch配体JAG 2是转录激活缺氧在HIF-1 α依赖的方式。如通过增加的icN 1水平和Notch靶基因HEY 1的诱导所测量的，低血糖JAG 2诱导导致肿瘤细胞中Notch活性升高。在原发性肿瘤材料中，JAG 2表达与血管发育和血管生成基因特征相关。与此一致，内皮细胞与缺氧乳腺癌细胞的共培养实验显示在乳腺癌细胞的JAG 2 siRNA处理后形成的毛细血管样管的数量减少。总之，这些结果表明，肿瘤细胞中JAG 2的低氧诱导介导了肿瘤和内皮细胞之间的低氧调节的串扰。Mol Cancer Res; 9（5）; 626-36. (C)2011年AACR。
Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on intracellular domain of the Notch1 receptor (icN1) stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1 alpha dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, coculture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells. Mol Cancer Res; 9(5); 626-36. (C) 2011 AACR.