title: 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 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.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Holmes
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.forename: Corrine Y X
authors.initials: CY
authors.lastname: Chua
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dunlap
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Liu
authors.forename: Niek
authors.initials: N
authors.lastname: Hugen
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Moore
authors.forename: David
authors.initials: D
authors.lastname: Cogdell
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hess
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D030161:Avian Proteins / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005813:Genes, Synthetic; D020571:Genes, sis; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000633:toxicity; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D019012:Integrin beta1 / Q000502:physiology*; D007381:Intermediate Filament Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology* / Q000633:toxicity; D011991:Receptors, Virus / Q000235:genetics; D012190:Retroviridae; D015398:Signal Transduction / Q000502:physiology; D000099200:Scaffold Protein ILK
chemical_list: D030161:Avian Proteins; D020672:I-kappa B Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D019012:Integrin beta1; D007381:Intermediate Filament Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D017346:Protein Serine-Threonine Kinases; D011991:Receptors, Virus; D000099200:Scaffold Protein ILK; C577484:NES protein, human; C000606204:NFKBIA protein, human; C577485:Nes protein, mouse; C000606205:Nfkbia protein, mouse; C088745:Tva receptor