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Downregulation of CCN3 expression as a potential mechanism for melanoma progression

Oncogene volume 27, pages 2552–2560 (2008)Cite this article

Abstract

Coculture of human melanocytes with keratinocytes upregulates CCN3, a matricellular protein critical to maintenance of normal homeostasis of melanocytes in the skin. CCN3 affects two fundamental features of melanocyte physiology: it inhibits melanocyte proliferation and stimulates their adhesion to the basement membrane. Here we report that expression of CCN3 is downregulated in advanced melanomas. Aggressive melanoma cell lines did not respond to treatment with CCN3 inducers, such as interleukin-1β (IL-1β), while less aggressive melanoma cell lines responded similarly to melanocytes. Immunostaining analyses revealed that CCN3 was present in melanoma cells close to the epidermal–dermal interface, but not in melanoma cells that had invaded deep into the dermis or had metastasized to lymph nodes. Contrary to our expectations, overexpression of CCN3 in 1205Lu metastatic melanoma cells did not affect their adhesion to collagen IV. However, CCN3 decreased the transcription and activation of matrix metalloproteinases and suppressed the invasion of 1205Lu melanoma cells. These results suggest that the lack of CCN3 in advanced melanoma cells contributes to their invasive phenotype. Whereas major matricellular proteins, such as osteopontin, tenascin or secreted protein acidic and rich in cysteine (SPARC), are strongly upregulated in melanoma cells; CCN3 is the first member of this family that is downregulated.

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Acknowledgements

We thank Kate M Belser for technical assistance. This work was supported by grants from the National Institutes of Health (CA76674, CA80999, CA47159, CA76674, CA25874 and CA10815) and was partially supported by funds from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

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Authors and Affiliations

  1. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA

    M Fukunaga-Kalabis, G Martinez, S M Telson, Z-J Liu, K Balint & M Herlyn

  2. Department of Dermatology and Venerology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    I Juhasz

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    D E Elder

  4. Laboratoire d'Oncologie Virale et Moléculaire, Université Paris 7-D. Diderot, Paris, France

    B Perbal

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  1. M Fukunaga-Kalabis
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  4. Z-J Liu
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  9. M Herlyn
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Correspondence to M Herlyn.

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

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Fukunaga-Kalabis, M., Martinez, G., Telson, S. et al. Downregulation of CCN3 expression as a potential mechanism for melanoma progression. Oncogene 27, 2552–2560 (2008). https://doi.org/10.1038/sj.onc.1210896

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  • DOI: https://doi.org/10.1038/sj.onc.1210896

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