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Insulin-Like Growth Factor Binding Protein-2 Binding to Extracellular Matrix Plays a Critical Role in Neuroblastoma Cell Proliferation, Migration, and Invasion

Murdoch Childrens Research Institute (V.C.R., B.S.S., E.A., S.I.Y., G.A.W.), Centre for Hormone Research and Department of Paediatrics (V.C.R., B.S.S., E.A., S.I.Y., G.A.W.), University of Melbourne, Parkville 3052, Victoria, Australia; University Children’s Hospital (B.S.S., M.B.R.), 72076 Tübingen, Germany; Institute of Animal Breeding (A.H.), Ludwig-Maximilian University, D-81377 Munich, Germany; and Department of Medicine (L.A.B.), University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia

Address all correspondence and requests for reprints to: Vincenzo C. Russo, Ph.D., Centre for Hormone Research, Murdoch Childrens Research Institute, University of Melbourne, Parkville 3052, Victoria, Australia. E-mail: vince.russo{at}mcri.edu.au.

IGF binding proteins (IGFBPs) modulate IGF cellular bioavailability and may directly regulate tumor growth and invasion. We have previously shown that IGFBP-2 binds and localizes IGF-I to the pericellular matrix and have provided some evidence suggesting that the heparin binding domain (HBD) or the arginine-glycine-aspartic acid (RGD) integrin binding motif may be involved in these interactions. However, the precise mechanisms involved remain to be elucidated. We therefore mutated the HBD or RGD sequence of IGFBP-2 and investigated consequent effects on extracellular matrix (ECM) binding, IGF-induced proliferation, and migration of neuroblastoma cells. IGFBP-2 and its arginine-glycine-glutamic acid (RGE) mutant similarly bound ECM components, whereas binding of mutant HBD-IGFBP-2 to each of the ECM substrates was markedly reduced by 70–80% (P < 0.05). IGF-I (100 ng/ml) increased incorporation of ³H-thymidine in neuroblastoma SK-N-SHEP cells by approximately 30%, an effect blunted by exogenously added native or either mutant IGFBP-2. Overexpression of IGFBP-2 and its RGE mutant potently promoted SHEP cell proliferation (5-fold), whereas SHEP cell proliferation was negligible when HBD-IGFBP-2 was overexpressed. Addition or overexpression of IGFBP-2 and its RGE mutant potently (P < 0.05) enhanced SHEP cell migration/invasion through the ECM. However, overexpression of the HBD-IGFBP-2 mutant potently inhibited (50–60%) SHEP cell invasion through ECM. Thus, IGFBP-2, which binds to the ECM, enhances proliferation and metastatic behavior of neuroblastoma cells, functions that directly or indirectly use the HBD but not the integrin binding sequence. Our novel findings thus point to a key role for the HBD of IGFBP-2 in the control and regulation of neuroblastoma growth and invasion.

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