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Annexin A1 in primary tumors promotes melanoma dissemination

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Abstract

Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03–9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12–26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.

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Acknowledgments

We are grateful to Dr François Boulay (UMR5092, CEA Grenoble) for gifting the FPR HL-60 cells and to Laurie Joumard for her participation in the molecular characterization of melanoma cell lines for FPR status. This work was supported by the Ligue Régionale Contre le Cancer and the Société Française de Dermatologie. ZB received fellowship support via a Conseil Régional d’Auvergne-backed ‘Innovative funds’ project.

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Authors and Affiliations

  1. Clermont-Ferrand Université, Université d’Auvergne, INSERM U990, Imagerie Moléculaire et Thérapie Vectorisée, BP 184, 63000, Clermont-Ferrand, France

    Zied Boudhraa, Fabien Rondepierre, Anna Trzeciakiewicz, Bernadette Bouchon, Janine Papon, Jean-Michel Chezal, Elisabeth Miot-Noirault, Mathilde Bonnet, Michel D’Incan & Françoise Degoul

  2. Department of Biostatistics, Université d’Auvergne, 63001, Clermont-Ferrand, France

    Lemlih Ouchchane

  3. Department of Dermatology, CHU, Université d’Auvergne, 63001, Clermont-Ferrand, France

    Roselyne Kintossou, Sandrine Mansard & Michel D’Incan

  4. Department of Pathology, CHU, Université d’Auvergne, 63001, Clermont-Ferrand, France

    Frederic Franck, Juliette Joubert-Zakeyh & Pierre Dechelotte

  5. Department of Dermatopathology, Edouard Herriot Hospital Group, 69437, Lyon Cedex 03, France

    Jean Kanitakis

  6. Department of Dermatopathology, CHU St-Etienne, 42055, St-Priest-en-Jarez, France

    Bruno Labeille & Jean Luc Perrot

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  1. Zied Boudhraa
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  2. Fabien Rondepierre
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  6. Frederic Franck
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  7. Jean Kanitakis
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  8. Bruno Labeille
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  9. Juliette Joubert-Zakeyh
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  10. Bernadette Bouchon
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  11. Jean Luc Perrot
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  13. Janine Papon
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  14. Pierre Dechelotte
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  15. Jean-Michel Chezal
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  16. Elisabeth Miot-Noirault
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  17. Mathilde Bonnet
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  18. Michel D’Incan
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  19. Françoise Degoul
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Corresponding author

Correspondence to Françoise Degoul.

Additional information

Zied Boudhraa and Fabien Rondepierre have contributed equally to this work.

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10585_2014_9665_MOESM1_ESM.pdf

300 pmol ANXA1 and control siRNA were injected at days 11, 14 and 18 into B16Bl6 tumors obtained after grafting 3x105 cells into C57BL6 mice. For each treatment, 20 mice were sacrificed at day 23. Proteins were extracted from each tumor. qPCR and western blotting analyses revealed a significant decrease in steady-state levels of ANXA1 and mRNA protein levels, respectively, as quantified by the ANXA1/26S and ANXA1/GAPDH ratios (* Student’s t-test, p<0.05). a.u. = arbitrary units. Supplementary material 1 (PDF 35 kb)

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Boudhraa, Z., Rondepierre, F., Ouchchane, L. et al. Annexin A1 in primary tumors promotes melanoma dissemination. Clin Exp Metastasis 31, 749–760 (2014). https://doi.org/10.1007/s10585-014-9665-2

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  • DOI: https://doi.org/10.1007/s10585-014-9665-2

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