Journal
ONCOGENE
Volume 33, Issue 23, Pages 3054-3063Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.267
Keywords
extracellular matrix; metalloprotease; metastasis; miRNA; TGF-beta
Funding
- Ministerio de Economia y Competitividad-Spain
- RTICC-Instituto de Salud Carlos III-Spain
- European Union
- BBVA foundation [2009 SGR1429, SAF2010-21171]
- Obra Social Cajastur-Asturias
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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 beta (TGF-beta) 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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