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Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

Oncogene volume 31, pages 1710–1722 (2012)Cite this article

Abstract

Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell–matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell–matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via β1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin β1, potentiating schwannoma's proliferation and cell–matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of anti-apoptotic AKT. Thus, IGFBP-1/integrin β1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.

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Acknowledgements

This work was supported by the CTF, Northcott Devon Medical Foundation and by Peninsula College of Medicine and Dentistry, Plymouth, UK. Pfizer supplied inhibitor.

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Authors and Affiliations

  1. Clinical Neurobiology, Peninsula College for Medicine and Dentistry, Plymouth, UK

    S Ammoun, M C Schmid, L Zhou, N Ristic, E Ercolano & C O Hanemann

  2. Department of Histopathology, Derriford Hospital, Plymouth, UK

    D A Hilton

  3. Department of Clinical Sciences North Bristol, IGFs and Metabolic Endocrinology, University of Bristol, Bristol, UK

    C M Perks

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  1. S Ammoun
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Correspondence to C O Hanemann.

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Ammoun, S., Schmid, M., Zhou, L. et al. Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival. Oncogene 31, 1710–1722 (2012). https://doi.org/10.1038/onc.2011.357

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