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

Kristen M Holmes; Matti Annala; Corrine Y X Chua; Sarah M Dunlap; Yuexin Liu; Niek Hugen; Lynette M Moore; David Cogdell; Limei Hu; Matti Nykter; Kenneth Hess; Gregory N Fuller; Wei Zhang

doi:10.1073/pnas.1120375109

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

Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3475-80. doi: 10.1073/pnas.1120375109. Epub 2012 Feb 15.

Authors

Kristen M Holmes¹, Matti Annala, Corrine Y X Chua, Sarah M Dunlap, Yuexin Liu, Niek Hugen, Lynette M Moore, David Cogdell, Limei Hu, Matti Nykter, Kenneth Hess, Gregory N Fuller, Wei Zhang

Affiliation

¹ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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 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-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytoma / genetics
Astrocytoma / metabolism
Avian Proteins / genetics
Brain Neoplasms / genetics
Brain Neoplasms / pathology*
Brain Neoplasms / therapy
Cell Line, Tumor
Disease Progression
Gene Expression Regulation, Neoplastic
Genes, Synthetic
Genes, sis
Genetic Therapy*
Genetic Vectors / administration & dosage
Genetic Vectors / therapeutic use*
Glioblastoma / genetics
Glioblastoma / pathology*
Glioblastoma / therapy
Humans
I-kappa B Proteins / genetics
I-kappa B Proteins / toxicity
Insulin-Like Growth Factor Binding Protein 2 / biosynthesis
Insulin-Like Growth Factor Binding Protein 2 / genetics
Insulin-Like Growth Factor Binding Protein 2 / physiology*
Insulin-Like Growth Factor Binding Protein 2 / toxicity
Integrin beta1 / physiology*
Intermediate Filament Proteins / genetics
Kaplan-Meier Estimate
Mice
Mice, Transgenic
NF-KappaB Inhibitor alpha
NF-kappa B / physiology*
Neoplasm Invasiveness
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Nerve Tissue Proteins / genetics
Nestin
Oligodendroglioma / genetics
Oligodendroglioma / metabolism
Prognosis
Protein Serine-Threonine Kinases / physiology*
Protein Serine-Threonine Kinases / toxicity
Receptors, Virus / genetics
Retroviridae
Signal Transduction / physiology

Substances

Avian Proteins
I-kappa B Proteins
Insulin-Like Growth Factor Binding Protein 2
Integrin beta1
Intermediate Filament Proteins
NES protein, human
NF-kappa B
NFKBIA protein, human
Neoplasm Proteins
Nerve Tissue Proteins
Nes protein, mouse
Nestin
Nfkbia protein, mouse
Receptors, Virus
Tva receptor
NF-KappaB Inhibitor alpha
integrin-linked kinase
Protein Serine-Threonine Kinases

Associated data

GEO/GSE35467