CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells
CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells
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DOI：
10.1016/j.celrep.2017.07.049
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发表时间：
2017-08-15
期刊：
影响因子：
8.8
通讯作者：
Pietras, Alexander
中科院分区：
文献类型：
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作者：
Johansson, Elinn;Grassi, Elisa S.;Pietras, Alexander
缺氧诱导因子增强胶质瘤的干细胞性，并且胶质瘤干细胞具有放大的缺氧反应，尽管其位于血管周围的小生境中。尽管如此，很少有人知道差异HIF调节干细胞与散装胶质瘤细胞。我们发现，干细胞标志物CD 44（CD 44 ICD）的细胞内结构域在缺氧时释放，结合HIF-2 α（而不是HIF-1 α），增强HIF靶基因激活，并且是缺氧诱导的神经胶质瘤干细胞所必需的。在胶质瘤小鼠模型中，CD 44仅限于缺氧和血管周围肿瘤区域，而在人类胶质瘤中，缺氧特征与CD 44相关。CD 44 ICD足以在血管周围氧张力下诱导缺氧信号，并且阻断CD 44裂解降低了表达CD 44的细胞中HIF-2 α的稳定性。我们的数据表明，干细胞标志物CD 44调节神经胶质瘤细胞的缺氧反应，干细胞样神经胶质瘤细胞的假缺氧表型是通过与CD 44相互作用稳定HIF-2 α而实现的，与氧无关。
Hypoxia-inducible factors enhance glioma stem-ness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2 alpha (but not HIF-1 alpha), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2 alpha stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2 alpha through interaction with CD44, independently of oxygen.