title: The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21.
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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Soria-Valles
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Guiu
authors.affiliation: Centre National de la Recherche Scientifique and Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia-Antipolis, France.
authors.forename: B
authors.initials: B
authors.lastname: Mari
authors.affiliation: 193;rea de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fueyo
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: R R
authors.initials: RR
authors.lastname: Gomis
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: C
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D058575:Decorin / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D058575:Decorin; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8