CD44 与 HIF-2α 相互作用调节坏死周围和血管周围神经胶质瘤细胞的缺氧表型。
CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells.
机构信息
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden.
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark.
出版信息
Cell Rep. 2017 Aug 15;20(7):1641-1653. doi: 10.1016/j.celrep.2017.07.049.
Hypoxia-inducible factors enhance glioma stemness, 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-2α (but not HIF-1α), 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-2α 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-2α through interaction with CD44, independently of oxygen.
缺氧诱导因子增强了神经胶质瘤干细胞干性，并且神经胶质瘤干细胞即使位于血管周龛位，也具有放大的缺氧反应。然而，关于干性与普通神经胶质瘤细胞中 HIF 的差异调节知之甚少。我们发现干细胞标志物 CD44 的细胞内结构域（CD44ICD）在缺氧时释放，与 HIF-2α（而非 HIF-1α）结合，增强 HIF 靶基因的激活，并在神经胶质瘤中诱导干性。在神经胶质瘤小鼠模型中，CD44 局限于缺氧和血管周肿瘤区域，在人类神经胶质瘤中，缺氧特征与 CD44 相关。CD44ICD 足以在血管周氧张力下诱导缺氧信号，并且阻断 CD44 切割会减少 CD44 表达细胞中 HIF-2α 的稳定。我们的数据表明，干细胞标志物 CD44 调节神经胶质瘤细胞的缺氧反应，并且通过与 CD44 相互作用稳定 HIF-2α，独立于氧，实现了类干细胞神经胶质瘤的假缺氧表型。
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