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  • Original Article
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CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

Oncogene volume 26, pages 6604–6618 (2007)Cite this article

Abstract

CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules.

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Acknowledgements

We are in debt to Vanessa Cerisano, Silvia Liciulli and Stefania Perdichizzi for their excellent technical assistance. We thank Professor MF Di Renzo, Laboratory of Cancer Genetics, University of Turin at IRCC, 10060 Candiolo (Turin), Italy, and Professor M Grano, University of Bari, Italy, for kindly providing us normal human osteoblast cultures. This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) (K Scotlandi) and ARC (Association pour la Recherche sur le Cancer) (A Bernard) and the European Project PROTHETS.

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Authors and Affiliations

  1. Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, Italy

    K Scotlandi, M Zuntini, M C Manara, M Sciandra, A Rocchi, S Benini, G Nicoletti & P Picci

  2. Unité INSERM UMR 576, Hôspital de l'Archet, Nice, Cedex 3, France

    G Bernard & A Bernard

  3. Sezione di Cancerologia, Dipt. di Patologia Sperimentale, Università di Bologna, Bologna, Italy

    P Nanni & P-L Lollini

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  1. K Scotlandi
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  2. M Zuntini
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  3. M C Manara
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  4. M Sciandra
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  5. A Rocchi
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  6. S Benini
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  7. G Nicoletti
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  8. G Bernard
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  9. P Nanni
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  10. P-L Lollini
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  11. A Bernard
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  12. P Picci
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Correspondence to K Scotlandi.

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

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Scotlandi, K., Zuntini, M., Manara, M. et al. CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. Oncogene 26, 6604–6618 (2007). https://doi.org/10.1038/sj.onc.1210481

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  • DOI: https://doi.org/10.1038/sj.onc.1210481

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