Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network
Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network
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DOI：
10.1073/pnas.1120375109
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发表时间：
2012-02-28
影响因子：
11.1
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Holmes, Kristen M.;Annala, Matti;Zhang, Wei
胰岛素样生长因子结合蛋白 2 (IGFBP2) 越来越被认为是一种神经胶质瘤癌基因，并成为治疗干预的目标。在这项研究中，我们使用综合方法来表征 IGFBP2 网络，将人类神经胶质瘤的转录分析与神经胶质细胞中的验证以及具有复制能力的 ASLV 长末端重复序列与剪接受体/tv-a 神经胶质瘤小鼠系统相结合。我们证明 IGFBP2 表达与整合素和整合素连接激酶 (ILK) 途径中的基因密切相关，并且这些基因与预后相关。我们进一步表明IGFBP2激活整合素β1和下游侵袭途径，需要ILK诱导细胞运动，并激活NF-kappa B。最重要的是，IGFBP2/整合素/ILK/NF-kappa B网络通过驱动神经胶质瘤进展作为体内生理活性信号通路发挥作用；干扰该途径中的任何一点都会显着抑制进展。这项研究的结果揭示了一条信号通路，该信号通路既具有针对性，又与提高神经胶质瘤患者的生存率高度相关。
Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin beta 1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-kappa B. Most significantly, the IGFBP2/integrin/ILK/NF-kappa B network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients.