Inositol-requiring enzyme 1α is a key regulator of angiogenesis and invasion in malignant glioma
Inositol-requiring enzyme 1α is a key regulator of angiogenesis and invasion in malignant glioma
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DOI：
10.1073/pnas.0914072107
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发表时间：
2010-08-31
影响因子：
11.1
通讯作者：
Moenner, Michel
中科院分区：
文献类型：
--
作者：
Auf, Gregor;Jabouille, Arnaud;Moenner, Michel
肌醇要求酶1 （IRE1）是近端内质网（ER）应激传感器和未折叠蛋白反应的中心介质。在人类胶质瘤模型中，IRE1 α的抑制与普遍的促血管生成因子如VEGF-A、IL-1 β、IL-6和IL-8的下调相关。抗血管生成基因转录的显著上调也很明显。这些转录本编码SPARC、decorin、thrombospontin -1和其他与间质分化和胶质瘤侵袭相关的基质蛋白。在体内，通过鸡绒毛膜-尿囊膜实验和小鼠原位脑模型，我们观察到在低表达IRE1的肿瘤中：(i)血管生成和血液灌注减少，（ii）生长速度下降，（iii）广泛侵袭和血管合用。这种表型变化始终与胶质瘤植入受体小鼠的总存活率增加有关。在ire1缺失的肿瘤中，IL-6的异位表达恢复了血管生成和中和血管合用，但没有逆转间充质/浸润细胞表型。因此，缺血反应性IRE1蛋白被认为是肿瘤新生血管和侵袭性的关键调节因子。
Inositol-requiring enzyme 1 (IRE1) is a proximal endoplasmic reticulum (ER) stress sensor and a central mediator of the unfolded protein response. In a human glioma model, inhibition of IRE1 alpha correlated with down-regulation of prevalent proangiogenic factors such as VEGF-A, IL-1 beta, IL-6, and IL-8. Significant up-regulation of antiangiogenic gene transcripts was also apparent. These transcripts encode SPARC, decorin, thrombospondin-1, and other matrix proteins functionally linked to mesenchymal differentiation and glioma invasiveness. In vivo, using both the chick chorio-allantoic membrane assay and a mouse orthotopic brain model, we observed in tumors under-expressing IRE1: (i) reduction of angiogenesis and blood perfusion, (ii) a decreased growth rate, and (iii) extensive invasiveness and blood vessel cooption. This phenotypic change was consistently associated with increased overall survival in glioma-implanted recipient mice. Ectopic expression of IL-6 in IRE1-deficient tumors restored angiogenesis and neutralized vessel cooption but did not reverse the mesenchymal/infiltrative cell phenotype. The ischemia-responsive IRE1 protein is thus identified as a key regulator of tumor neovascularization and invasiveness.