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The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21

Oncogene volume 33, pages 3054–3063 (2014)Cite this article

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A Correction to this article was published on 03 May 2019

Abstract

Matrix metalloproteinases (MMPs) have been traditionally implicated in cancer progression because of their ability to degrade the extracellular matrix. However, some members of the MMP family have recently been identified as proteases with antitumor properties. Thus, it has been described that collagenase-2 (MMP-8) has a protective role in tumor and metastasis progression, but the molecular mechanisms underlying these effects are unknown. We show herein that Mmp8 expression causes a decrease in miR-21 levels that in turn leads to a reduction in tumor growth and lung metastasis formation by MDA-MB-231 (4175) breast cancer cells. By using both in vitro and in vivo models, we demonstrate that the mechanism responsible for these MMP-8 beneficial effects involves cleavage of decorin by MMP-8 and a subsequent reduction of transforming growth factor β (TGF-β) signaling that controls miR-21 levels. In addition, miR-21 downregulation induced by MMP-8 increases the levels of tumor suppressors such as programmed cell death 4, which may also contribute to the decrease in tumor formation and metastasis of breast cancer cells overexpressing this metalloproteinase. These findings reveal a new signaling pathway for cancer regulation controlled by MMP-8, and contribute to clarify the molecular mechanisms by which tumor-defying proteases may exert their protective function in cancer and metastasis.

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Acknowledgements

We are very grateful to Dr JMP Freije and FG Osorio for helpful comments and to C Garabaya, MF Suárez y S Alvarez for their excellent technical assistance. We also thank the excellent support of the Nice-Sophia Antipolis Functional Genomics Platform. This work was supported by grants from Ministerio de Economía y Competitividad-Spain, RTICC-Instituto de Salud Carlos III-Spain, and European Union (FP7-Microenvimet). BBVA foundation, 2009 SGR1429 and SAF2010–21171 support to RRG was provided. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias. CL-O is an Investigator of the Botin Foundation.

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain

    C Soria-Valles, A Gutiérrez-Fernández & C López-Otín

  2. Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain,

    M Guiu & R R Gomis

  3. Centre National de la Recherche Scientifique and Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia-Antipolis, France

    B Mari

  4. Departamento de Biología Funcional, Área de Fisiología, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain

    A Fueyo

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  1. C Soria-Valles
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Correspondence to C López-Otín.

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Soria-Valles, C., Gutiérrez-Fernández, A., Guiu, M. et al. The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21. Oncogene 33, 3054–3063 (2014). https://doi.org/10.1038/onc.2013.267

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