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A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis

Oncogene volume 28, pages 4237–4248 (2009)Cite this article

Abstract

Hallmarks of malignant melanoma are its propensity to metastasize and its resistance to treatment, giving patients with advanced disease a poor prognosis. The transition of melanoma from non-invasive radial growth phase (RGP) to invasive and metastatically competent vertical growth phase (VGP) is a major step in tumor progression, yet the mechanisms governing this transformation are unknown. Matrix metalloproteinase-1 (MMP-1) is highly expressed by VGP melanomas, and is thought to contribute to melanoma progression by degrading type I collagen within the skin to facilitate melanoma invasion. Protease activated receptor-1 (PAR-1) is activated by MMP-1, and is also expressed by VGP melanomas. However, the effects of MMP-1 signaling through PAR-1 have not been examined in melanoma. Here, we demonstrate that an MMP-1/PAR-1 signaling axis exists in VGP melanoma, and is necessary for melanoma invasion. Introduction of MMP-1 into RGP melanoma cells induced gene expression associated with tumor progression and promoted invasion in vitro, and enhanced tumor growth and conferred metastatic capability in vivo. This study demonstrates that both the type I collagenase and PAR-1 activating functions of MMP-1 are required for melanoma progression, and suggests that MMP-1 may be a major contributor to the transformation of melanoma from non-invasive to malignant disease.

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Acknowledgements

We thank Shaun Coughlin (University of California, San Francisco, CA, USA) for his generous gift of the AP–PAR-1 construct. This work was supported by NIH grants CA-77267 and AR-26599 (to CEB), NIH grant T32-AI07363 (to JSB) and the Prouty Pilot Grant by the Friends of the Norris Cotton Cancer Center (to CEB).

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Authors and Affiliations

  1. Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA

    J S Blackburn, C I Coon & C E Brinckerhoff

  2. Department of Medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    I Liu & C E Brinckerhoff

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  1. J S Blackburn
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  2. I Liu
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  3. C I Coon
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  4. C E Brinckerhoff
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Correspondence to C E Brinckerhoff.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Blackburn, J., Liu, I., Coon, C. et al. A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene 28, 4237–4248 (2009). https://doi.org/10.1038/onc.2009.272

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