Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital, Entrance 78, SE-205 02 Malmö, Sweden.
Mol Cancer Res. 2011 May;9(5):626-36. doi: 10.1158/1541-7786.MCR-10-0508. Epub 2011 Mar 14.
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-1α 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.
几项研究揭示了缺氧与实体瘤中 Notch 激活之间的联系。虽然大多数报告都集中在 Notch1 受体的细胞内结构域（icN1）通过与 HIF 蛋白的直接相互作用而稳定，但对缺氧期间 Notch 配体的调节关注甚少。在这里，我们表明 Notch 配体 JAG2 在缺氧条件下以 HIF-1α 依赖性方式被转录激活。缺氧诱导的 JAG2 诱导导致肿瘤细胞中 Notch 活性增加，如 icN1 水平升高和 Notch 靶基因 HEY1 的诱导所测量的那样。在原发性肿瘤材料中，JAG2 表达与血管生成和血管生成基因特征相关。与此一致的是，内皮细胞与缺氧乳腺癌细胞的共培养实验显示，在乳腺癌细胞用 JAG2 siRNA 处理后，形成的毛细血管样管的数量减少。这些结果表明，肿瘤细胞中 JAG2 的缺氧诱导介导了肿瘤细胞和内皮细胞之间缺氧调节的交叉对话。
