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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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