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N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells

Oncogene volume 21, pages 4549–4557 (2002)Cite this article

Abstract

Neuroblastoma is a peripheral nervous system tumor that accounts for 8–10% of all solid childhood tumors. N-Myc is the most reliable prognostic indicator for neuroblastoma. Bcl-2 is detected in 40–60% of primary neuroblastoma tumors and demonstrates anti-apoptotic action by conferring resistance to chemotherapy and radiation treatment. In neuroblastoma cell lines, the coexpression of N-Myc and Bcl-2 leads to increased tumorigenic properties. Matrix metalloproteinases (MMPs) are endopeptidases that degrade a wide range of basement membrane components, a process important for tumor invasion. This study investigates the effect of N-Myc and Bcl-2 on MMP expression and activation. MMP-2 expression and secretion are increased in SHEP neuroblastoma cells expressing Bcl-2 alone (SHEP/Bcl-2 cells) or both N-Myc and Bcl-2 (SHEP/N-Myc/Bcl-2 cells). MMP-2 activity is increased in the SHEP/N-Myc/Bcl-2 cells yet remains unchanged in SHEP/Bcl-2 cells. TIMP-2 expression is high in SHEP/Bcl-2 cells, which likely inhibits MMP-2 activity, and absent in SHEP/N-Myc/Bcl-2 cells, allowing MMP-2 activity. Invasion is increased in SHEP/N-Myc/Bcl-2 cells and prevented by the use of a pharmacologic MMP-2 inhibitor. These data imply that N-Myc and Bcl-2 cooperate to increase the expression, secretion, and activation of MMP-2, which likely leads to a more tumorigenic phenotype due to increased MMP-2 mediated invasion.

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Acknowledgements

The authors thank Ms Judy Boldt for excellent secretarial assistance, Dr Tracy Schwab for helpful discussions, and Dr Bhumsoo Kim for aid in figure preparation. We would also like to thank Dr Eric Schwab and Ms Lisa McClean from the Oxidative Stress Core of the JDRF Center for the Study of Complications in Diabetes for assistance in performing MMP activity and cellular invasion assays. This work was supported by the National Institutes of Health (NIH T32 NS07222, RO1 NS36778) and the Program for Understanding Neurological Diseases (PFUND).

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Authors and Affiliations

  1. Department of Neurology, University of Michigan, Ann Arbor, 48109, Michigan, MI, USA

    Daniel Noujaim, Cynthia M van Golen, Alyssa Grauman & Eva L Feldman

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, Michigan, MI, USA

    Kenneth L van Golen

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Correspondence to Eva L Feldman.

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Noujaim, D., van Golen, C., van Golen, K. et al. N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells. Oncogene 21, 4549–4557 (2002). https://doi.org/10.1038/sj.onc.1205552

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