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CLEC12B Decreases Melanoma Proliferation by Repressing Signal Transducer and Activator of Transcription 3

  • Henri Montaudié
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France

    Department of Dermatology, Centre hospitalier universitaire (CHU) de Nice, Université Nice Côte d'Azur, Nice, France
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  • Laura Sormani
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Bérengère Dadone-Montaudié
    Affiliations
    Department of Pathology, Université Nice Côte d'Azur, Nice, France

    Laboratory of Solid Tumors Genetics, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284/ Institut national de la santé et de la recherche médicale (INSERM) U1081, CHU Nice, Université Nice Côte d'Azur, Nice, France
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  • Marjorie Heim
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Nathalie Cardot-Leccia
    Affiliations
    Department of Pathology, Université Nice Côte d'Azur, Nice, France
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  • Meri K. Tulic
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Guillaume Beranger
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Anne-Sophie Gay
    Affiliations
    IPMC, CNRS, Université Côte d'Azur, Sophia Antipolis, France
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  • Delphine Debayle
    Affiliations
    IPMC, CNRS, Université Côte d'Azur, Sophia Antipolis, France
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  • Yann Cheli
    Affiliations
    Team 1, Biology and pathologies of melanocytes, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Jérémy H. Raymond
    Affiliations
    Normal and Pathological Development of Melanocytes, Institut Curie, Institut national de la santé et de la recherche médicale (INSERM) U1021, PSL Research University, Paris, France

    UMR 3347, CNRS, Université Paris-Saclay, Paris, France

    Equipe Labellisée Ligue Contre le Cancer, Paris, France
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  • Pierre Sohier
    Affiliations
    Normal and Pathological Development of Melanocytes, Institut Curie, Institut national de la santé et de la recherche médicale (INSERM) U1021, PSL Research University, Paris, France

    UMR 3347, CNRS, Université Paris-Saclay, Paris, France

    Equipe Labellisée Ligue Contre le Cancer, Paris, France
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  • Valérie Petit
    Affiliations
    Normal and Pathological Development of Melanocytes, Institut Curie, Institut national de la santé et de la recherche médicale (INSERM) U1021, PSL Research University, Paris, France

    UMR 3347, CNRS, Université Paris-Saclay, Paris, France

    Equipe Labellisée Ligue Contre le Cancer, Paris, France
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  • Stéphane Rocchi
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France
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  • Franck Gesbert
    Affiliations
    Normal and Pathological Development of Melanocytes, Institut Curie, Institut national de la santé et de la recherche médicale (INSERM) U1021, PSL Research University, Paris, France

    UMR 3347, CNRS, Université Paris-Saclay, Paris, France

    Equipe Labellisée Ligue Contre le Cancer, Paris, France
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  • Author Footnotes
    10 These authors contributed equally to this work.
    Lionel Larue
    Footnotes
    10 These authors contributed equally to this work.
    Affiliations
    Normal and Pathological Development of Melanocytes, Institut Curie, Institut national de la santé et de la recherche médicale (INSERM) U1021, PSL Research University, Paris, France

    UMR 3347, CNRS, Université Paris-Saclay, Paris, France

    Equipe Labellisée Ligue Contre le Cancer, Paris, France
    Search for articles by this author
  • Author Footnotes
    10 These authors contributed equally to this work.
    Thierry Passeron
    Correspondence
    Correspondence: Thierry Passeron, Department of Dermatology and Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, 151 route Saint-Antoine de Ginestière, 06200 Nice, France.
    Footnotes
    10 These authors contributed equally to this work.
    Affiliations
    Team 12, Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut national de la santé et de la recherche médicale (INSERM) U1065, Université Nice Côte d'Azur, Nice, France

    Department of Dermatology, Centre hospitalier universitaire (CHU) de Nice, Université Nice Côte d'Azur, Nice, France
    Search for articles by this author
  • Author Footnotes
    10 These authors contributed equally to this work.
      The potential role of CLEC12B, a gene predominantly expressed by skin melanocytes discovered through transcriptomic analysis, in melanoma is unknown. In this study, we show that CLEC12B expression is lower in melanoma and melanoma metastases than in melanocytes and benign melanocytic lesions and that its decrease correlates with poor prognosis. We further show that CLEC12B recruits SHP2 phosphatase through its immunoreceptor tyrosine-based inhibition motif domain, inactivates signal transducer and activator of transcription 1/3/5, increases p53/p21/p27 expression/activity, and modulates melanoma cell proliferation. The growth of human melanoma cells overexpressing CLEC12B in nude mice after subcutaneous injection is significantly decreased compared with that in the vehicle control group and is associated with decreased signal transducer and activator of transcription 3 phosphorylation and increased p53 levels in the tumors. Reducing the level of CLEC12B had the opposite effect. We show that CLEC12B represses the activation of the signal transducer and activator of transcription pathway and negatively regulates the cell cycle, providing a proliferative asset to melanoma cells.

      Abbreviations:

      ITIM (immunoreceptor tyrosine-based inhibition motif), Ov (overexpressing vector), Sh (silencing vector), STAT (signal transducer and activator of transcription), WT (wild-type)
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