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

Abstract

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 replicationcompetent 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 β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB 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. E levated insulin-like growth factor-binding protein 2 (IGFBP2) expression is found in many malignancies and can often serve as a prognostic factor (1). It is one of the most consistently elevated proteins in high-grade glioma, and high IGFBP2 expression is directly correlated with poor survival (2, 3). The finding that IGFBP2 is a driver of glioma development and progression in a spontaneous mouse model has provided the most convincing evidence of the significance of IGFBP2 in glioma (4). Given the clinical challenge of treating glioma and the lack of effective therapies, the elucidation of key protein-signaling networks that are essential to tumor growth and maintenance, such as IGFBP2, could provide new approaches to therapeutic intervention and significantly affect clinical outcome.IGFBP2 is a member of the IGF system in which it binds and modulates IGF1 and IGF2 activity (5); however, IGFBP2 is better known for its IGF-independent roles in cancer, such as integrin binding through an arginine-glycine-aspartic acid (RGD) motif in the C terminus (6, 7). The interaction of IGFBP2 with integrin α5 has been reported to promote cellular de-adhesion and migration in Ewing's sarcoma (8), and we previously found that integrin α5 binding to IGFBP2 is responsible for the promigratory characteristics of glioma cells (7). Integrins transduce signaling through proteins such as integrin-linked kinase (ILK), which binds to the cytoplasmic domains of β1 and β3 integrins (9). ILK contributes to the oncogenic phenotype by stimulating invasion and migration, encouraging anchorage-independent growth, and inducing tumor angiogenesis (10). Although the function of ILK has been intimately associated with integrin function, no association with IGFBP2 has been reported.IGFBP2 has been reported to influence multiple transcriptional factors, including the up-regulation of NF-κB (6), which activates the transcription of an array of cancer-pro...

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