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首页> 外文期刊>Journal of Cellular Physiology >Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells.
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Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells.

机译：刺猬/ GLI1调节IGF恶性的依赖行为神经胶质瘤干细胞。

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摘要

A population of tumorigenic, chemoresistant, and radioresistant cancer stem cells is postulated to contribute to the aggressive and fatal clinical course of glioblastomas. Activation of the Hedgehog (HH) pathway and increased expression of its downstream effector GLI1 are driving factors of glioma tumorigenicity and glioma stem cell (GSC) biology. In this study, we describe a dependence of insulin-like growth factor (IGF) signaling on active HH/GLI1 in GSCs. Insulin receptor substrate 1 (IRS1) was identified as a target of the GLI1 transcription factor and inhibition of GLI1 was sufficient to obstruct IRS1 protein expression and IGF-I induced mitogen-activated protein kinase (MAPK) activation. Suppression of GLI1 activity decreased the responsiveness of GSCs to IGF-I stimulation and constrained IGF-I dependent GSC proliferation, clonogenicity, invasion, and angiogenesis. In addition, blockade of the HH/GLI1 and IGF pathways countered the intrinsic and acquired resistance of GSCs to temozolomide. These results provide further insight into the oncogenic mechanisms of the HH pathway in glioblastoma and demonstrate a cooperative signaling axis between the HH/GLI1 and IGF pathways to propagate malignant GSC phenotypes.
机译：肿瘤发生的人口,chemoresistant,抗放射性的癌症干细胞假说为积极的和致命的临床恶性胶质瘤。刺猬(HH)途径和表达增加它的下游效应GLI1驱动因素神经胶质瘤的致瘤性和神经胶质瘤干细胞(GSC)生物学。依赖胰岛素样生长因子(IGF)HH / GLI1 gsc信号在活跃。受体底物1 (IRS1)被确认为一个GLI1转录因子和的目标抑制GLI1足以阻碍IRS1蛋白质表达和IGF-I诱导增殖蛋白激酶(MAPK)激活。减少IGF-I gsc的响应性刺激和约束IGF-I GSC的依赖增殖,clonogenicity、入侵和血管生成。HH和IGF通路/ gli反击的内在和获得性耐药的gsc temozolomide。这些结果提供进一步的深入了解HH途径的致癌机制胶质母细胞瘤和展示合作信号HH / GLI1和IGF之间的轴途径传播恶性GSC表型。

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