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Open Access Research article

Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression

Carine Nyalendo1, Hervé Sartelet2, Stéphane Barrette3, Shigeru Ohta4, Denis Gingras1 and Richard Béliveau1*

Author Affiliations

1 Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centreville, Montréal, Québec H3C 3P8, Canada

2 Département de Pathologie, CHU Sainte-Justine, Montréal, Québec, Canada

3 Département de Pédiatrie CHU Sainte-Justine, Montréal, Québec, Canada

4 Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga, Japan

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BMC Cancer 2009, 9:422  doi:10.1186/1471-2407-9-422

Published: 4 December 2009

Abstract

Background

Neuroblastoma is a pediatric tumor of neural crest cells that is clinically characterized by its variable evolution, from spontaneous regression to malignancy. Despite many advances in neuroblastoma research, 60% of neuroblastoma, which are essentially metastatic cases, are associated with poor clinical outcome due to the lack of effectiveness of current therapeutic strategies. Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), an enzyme involved in several steps in tumor progression, has previously been shown to be associated with poor clinical outcome for neuroblastoma. Based on our recent demonstration that MT1-MMP phosphorylation is involved in the growth of fibrosarcoma tumors, we examined the potential role of phosphorylated MT1-MMP in neuroblastoma progression.

Methods

Tyrosine phosphorylated MT1-MMP was immunostained on tissue microarray samples from 55 patients with neuroblastoma detected by mass screening (known to be predominantly associated with favourable outcome), and from 234 patients with standard diagnosed neuroblastoma. In addition, the effects of a non phosphorylable version of MT1-MMP on neuroblastoma cell migration and proliferation were investigated within three-dimensional collagen matrices.

Results

Although there is no correlation between the extent of tyrosine phosphorylation of MT1-MMP (pMT1-MMP) and MYCN amplification or clinical stage, we observed greater phosphorylation of pMT1-MMP in standard neuroblastoma, while it is less evident in neuroblastoma from mass screening samples (P = 0.0006) or in neuroblastoma samples from patients younger than one year (P = 0.0002). In vitro experiments showed that overexpression of a non-phosphorylable version of MT1-MMP reduced MT1-MMP-mediated neuroblastoma cell migration and proliferation within a three-dimensional type I collagen matrix, suggesting a role for the phosphorylated enzyme in the invasive properties of neuroblastoma cells.

Conclusion

Overall, these results suggest that tyrosine phosphorylated MT1-MMP plays an important role in neuroblastoma progression and that its expression is preferentially observed in tumor specimens from neuroblastoma patients showing poor clinical outcome.