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

• Published in: Oncogene Vol. 33; no. 23; pp. 3054 - 3063
• Main Authors: Soria-Valles, C, Gutiérrez-Fernández, A, Guiu, M, Mari, B, Fueyo, A, Gomis, R R, López-Otín, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2014; Nature Publishing Group
• Subjects: 631/67/1347; 631/67/322; 631/80/86; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer cells; Cell Biology; Cell death; Cell Line, Tumor; Cells; Collagen; Collagenase; Collagenases; Decorin; Decorin - metabolism; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Neoplastic; Health aspects; Human Genetics; Humans; Internal Medicine; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Matrix metalloproteinase; Matrix Metalloproteinase 8 - metabolism; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Metastasis; Mice; Mice, Nude; MicroRNAs - metabolism; Molecular modelling; Neoplasm Metastasis; Neutrophil collagenase; Oncology; original-article; Physiological aspects; RNA, Small Interfering - pharmacology; Signal Transduction; Transforming growth factor-b; Tumors; Xenograft Model Antitumor Assays; miRNA; TGF-β; metalloprotease; metastasis; extracellular matrix
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.267

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.