Type I collagen-induced pro-MMP-2 activation is differentially regulated by H-Ras and N-Ras in human breast epithelial cells.
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 alpha2, 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.
Kim
In Young
IY
College of Pharmacy, Duksung Women's University, Seoul 132-714, Korea.
Jeong
Seo-Jin
SJ
Kim
Eun-Sook
ES
Kim
Seung Hee
SH
Moon
Aree
A
D002460:Cell Line; D024042:Collagen Type I / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D039423:Integrin alpha1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D024042:Collagen Type I; D004792:Enzyme Precursors; D039423:Integrin alpha1; D019012:Integrin beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D018631:ras Proteins