TY - JOUR
T1 - 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
AU - Holmes, Kristen M.
AU - Annala, Matti
AU - Chua, Corrine Y.X.
AU - Dunlap, Sarah M.
AU - Liu, Yuexin
AU - Hugen, Niek
AU - Moore, Lynette M.
AU - Cogdell, David
AU - Hu, Limei
AU - Nykter, Matti
AU - Hess, Kenneth
AU - Fuller, Gregory N.
AU - Zhang, Wei
PY - 2012/2/28
Y1 - 2012/2/28
N2 - 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 gliomawith validation in glial cells and the replicationcompetent ASLV long terminal repeatwith 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.
AB - 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 gliomawith validation in glial cells and the replicationcompetent ASLV long terminal repeatwith 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.
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U2 - 10.1073/pnas.1120375109
DO - 10.1073/pnas.1120375109
M3 - Article
C2 - 22345562
AN - SCOPUS:84863261004
VL - 109
SP - 3475
EP - 3480
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 9
ER -