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Type I Collagen-induced Pro-MMP-2 Activation is Differentially Regulated by H-Ras and N-Ras in Human Breast Epithelial Cells

  • Kim, In-Young (College of Pharmacy, Duksung Women's University) ;
  • Jeong, Seo-Jin (College of Pharmacy, Duksung Women's University) ;
  • Kim, Eun-Sook (College of Pharmacy, Duksung Women's University) ;
  • Kim, Seung-Hee (Department of Toxicology, National Institute of Toxicological Research) ;
  • Moon, A-Ree (College of Pharmacy, Duksung Women's University)
  • Published : 2007.09.30

Abstract

Tumor cell invasion and metastasis are often associated with matrix metalloproteinases (MMPs), among which MMP-2 and MMP-9 are of central importance. We previously showed that H-Ras, but not N-Ras, induced invasion of MCF10A human breast epithelial cells in which the enhanced expression of MMP-2 was involved. MMP-2 is produced as a latent pro-MMP-2 (72 kDa) to be activated resulting the 62 kDa active MMP-2. The present study investigated if H-Ras and/or N-Ras induces pro-MMP-2 activation of MCF10A cells when cultured in two-dimensional gel of type I collagen. Type I collagen induced activation of pro-MMP-2 only in H-Ras MCF10A cells but not in N-Ras MCF10A cells. Induction of active MMP-2 by type I collagen was suppressed by blocking integrin ${\alpha}2$, indicating the involvement of integrin signaling in pro-MMP-2 activation. Membrane-type (MT)1-MMP and tissue inhibitor of metalloproteinase (TIMP)-2 were up-regulated by H-Ras but not by N-Ras in the type I collagen-coated gel, suggesting that H-Ras-specific up-regulation of MT1-MMP and TIMP-2 may lead to the activation of pro-MMP-2. Since acquisition of pro-MMP-2 activation can be associated with increased malignant progression, these results may help understanding the mechanisms for the cell surface matrix-degrading potential which will be crucial to the prognosis and therapy of breast cancer metastasis.

Keywords

References

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