Tumor hypoxia is associated with poor patient survival and is a characteristic of glioblastoma. Notch signaling is implicated in maintaining glioma stem-like cells (GSCs) within the hypoxic niche, although the molecular mechanisms linking hypoxia to Notch activation have not been clearly delineated. Here we show that Vasorin is a critical link between hypoxia and Notch signaling in GSCs. Vasorin is preferentially induced in GSCs by a HIF1α/STAT3 co-activator complex and stabilizes Notch1 protein at the cell membrane. This interaction prevents Numb from binding Notch1, rescuing it from Numb-mediated lysosomal degradation. Thus, Vasorin acts as a switch to augment Notch signaling under hypoxic conditions. Vasorin promotes tumor growth and reduces survival in mouse models of glioblastoma, and its expression correlates with increased aggression of human gliomas. These findings provide mechanistic insights into how hypoxia promotes Notch signaling in glioma and identify Vasorin as a potential therapeutic target.

中文翻译：

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Vasorin 的缺氧诱导调节 Notch1 周转以维持胶质瘤干细胞样细胞。

肿瘤缺氧与患者生存率低有关，并且是胶质母细胞瘤的一个特征。Notch 信号与维持缺氧生态位内的胶质瘤干细胞样细胞 (GSC) 有关联，尽管将缺氧与 Notch 激活联系起来的分子机制尚未明确描述。在这里，我们表明血管素是 GSC 中缺氧和 Notch 信号传导之间的关键环节。Vasorin 优先在 GSC 中被 HIF1α/STAT3 共激活剂复合物诱导，并稳定细胞膜上的 Notch1 蛋白。这种相互作用可防止 Numb 与 Notch1 结合，从而将其从 Numb 介导的溶酶体降解中解救出来。因此，Vasorin 作为开关在缺氧条件下增强 Notch 信号。Vasorin 促进肿瘤生长并降低胶质母细胞瘤小鼠模型的存活率，并且其表达与人类神经胶质瘤的侵袭性增加相关。这些发现为缺氧如何促进神经胶质瘤中的 Notch 信号传导提供了机制见解，并将 Vasorin 确定为潜在的治疗靶点。