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HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1

Oncogene volume 24, pages 1423–1433 (2005)Cite this article

Abstract

The matrix fibronectin protein is a multifunctional adhesive molecule that promotes migration and invasiveness of many tumors including melanomas. Increased fibronectin synthesis has been associated with the metastatic potential of melanoma cells; however, the molecular mechanisms underlying fibronectin overexpression during melanoma development are poorly understood. We report that hepatocyte growth factor/scatter factor (HGF) induces fibronectin expression and its extracellular assembly on the surface of melanoma cells through activation of mitogen-activated protein (MAP) kinase pathway, and induction and transcriptional activation of Early growth response-1 (Egr-1). Inhibition of B-RAF/MAP kinase pathway by dominant-negative mutants and by U0126-abrogated HGF-induced Egr-1, and chromatin immunoprecipitation showed that Egr-1 is bound to the fibronectin promoter in response to HGF. Exogenously expressed Egr-1 increased fibronectin levels, while blockage of Egr-1 activation by expression of the Egr-1 corepressor NAB2 interfered with the upregulation of fibronectin synthesis induced by HGF, indicating that Egr-1 exerts a significant role in fibronectin expression in response to HGF. Finally, analysis of the expression pattern of fibronectin in melanoma cells demonstrated that fibronectin levels are correlated with constitutive MAP kinase signaling. Our data define a novel mechanism that might have important implications in regulation of melanoma progression by autocrine HGF signaling or by constitutive activation of MAP kinase pathway.

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Acknowledgements

We are grateful to Véronique Baron and Corine Bertolotto for helpful discussions and Edith Aberdam for technical advice. We thank David Cohen, Alain Eychene, Jacques Pouysségur, Dan Mercola and Peter E Shaw for providing cDNAs, and Meenhard Herlyn for 1205Lu melanoma cell line. This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and the Association pour la Recherche sur le Cancer (ARC), grant no 4709. CG is a recipient of a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche (France).

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  1. Markus U Ehrengruber

    Present address: Kantonsschule Hohe Promenade, Promenadengasse 11, CH-8001, Zurich, Switzerland

Authors and Affiliations

  1. INSERM Unité 597, Biologie et Pathologies des Cellules Mélanocytaires, ‘équipe labellisée la Ligue 2001’, IFR 50, 06107, Nice, Cédex 2, France

    Cédric Gaggioli, Guillaume Robert, Patricia Abbe, Jean-Paul Ortonne, Robert Ballotti & Sophie Tartare-Deckert

  2. INSERM Unité 576, Hôpital de l'Archet, 06202, Nice, France

    Marcel Deckert & Michelle Batoz

  3. Brain Research Institute, University of Zurich, CH-8057, Zurich, Switzerland

    Markus U Ehrengruber

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  1. Cédric Gaggioli
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Correspondence to Sophie Tartare-Deckert.

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Gaggioli, C., Deckert, M., Robert, G. et al. HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1. Oncogene 24, 1423–1433 (2005). https://doi.org/10.1038/sj.onc.1208318

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