Abstract
The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native α3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11-deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte–cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native α3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.
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Acknowledgements
We thank Takako Sasaki from the Max-Planck-Institute for Biochemistry, Munich, Germany for his help. This study was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Ligue Nationale Française contre le Cancer and the Comités du Haut-Rhin et du Bas-Rhin (équipe labellisée), the European Commission (FP6 LSHC-CT-2003-503297; Cancer Degradome Project), the Institut National du Cancer, Fond National pour la Santé ACI 2004 Cancéropôle Grand-Est and the ‘Ruban Rose’ prize. EM was a recipient of an EU fellowship.
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Motrescu, E., Blaise, S., Etique, N. et al. Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions. Oncogene 27, 6347–6355 (2008). https://doi.org/10.1038/onc.2008.218
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DOI: https://doi.org/10.1038/onc.2008.218
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