High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

Borrirukwanit, Kulrut, Pavasant, Prasit, Blick, Tony, Lafleur, Marc, & Thompson, Erik (2014) High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2). Cancer Cell International, 14(99), pp. 1-13.

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Abstract

Background

Matrix metalloproteinase-2 (MMP-2) is an endopeptidase that facilitates extracellular matrix remodeling and molecular regulation, and is implicated in tumor metastasis. Type I collagen (Col I) regulates the activation of MMP-2 through both transcriptional and post-transcriptional means; however gaps remain in our understanding of the involvement of collagen-binding ?1 integrins in collagen-stimulated MMP-2 activation.

Methods

Three ?1 integrin siRNAs were used to elucidate the involvement of ?1 integrins in the Col I-induced MMP-2 activation mechanism. ?1 integrin knockdown was analyzed by quantitative RT-PCR, Western Blot and FACS analysis. Adhesion assay and collagen gel contraction were used to test the biological effects of ?1 integrin abrogation. MMP-2 activation levels were monitored by gelatin zymography.

Results

All three ?1 integrin siRNAs were efficient at ?1 integrin knockdown and FACS analysis revealed commensurate reductions of integrins ?2 and ?3, which are heterodimeric partners of ?1, but not ?V, which is not. All three ?1 integrin siRNAs inhibited adhesion and collagen gel contraction, however only the siRNA showing the greatest magnitude of ?1 knockdown inhibited Col I-induced MMP-2 activation and reduced the accompanying upregulation of MT1-MMP, suggesting a dose response threshold effect. Re-transfection with codon-swapped ?1 integrin overcame the reduction in MMP-2 activation induced by Col-1, confirming the ?1 integrin target specificity. MMP-2 activation induced by TPA or Concanavalin A (Con A) was not inhibited by ?1 integrin siRNA knockdown.

Conclusion

Together, the data reveals that strong abrogation of ?1 integrin is required to block MMP-2 activation induced by Col I, which may have implications for the therapeutic targeting of ?1 integrin.

Impact and interest:

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ID Code: 88731
Item Type: Journal Article
Refereed: Yes
Keywords: Integrin; Matrix metalloproteinase; MMP-2 activation; Type I collagen; Invasion and metastasis
DOI: 10.1186/s12935-014-0099-3
ISSN: 1475-2867
Funding:
Copyright Owner: Copyright 2014 Borrirukwanit et al.; licensee BioMed Central Ltd.
Copyright Statement: This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public
Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this
article, unless otherwise stated.
Deposited On: 30 Oct 2015 00:58
Last Modified: 30 Oct 2015 00:58

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