Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-[kappa]B network

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (9), p.3475
• Main Authors: Holmes, Kristen M, Annala, Matti, Chua, Corrine Y X, Dunlap, Sarah M, Liu, Yuexin, Hugen, Niek, Moore, Lynette M, Cogdell, David, Hu, Limei, Nykter, Matti, Hess, Kenneth, Fuller, Gregory N, Zhang, Wei
• Format: Article
• Language: English
• Subjects: Cells; Gene expression; Insulin-like growth factors; Proteins; Rodents
• ISSN: 0027-8424; 1091-6490

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 β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-...B. Most significantly, the IGFBP2/integrin/ILK/NF-...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. (ProQuest: ... denotes formulae/symbols omitted.)