Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1

Oncogene. 2000 Jan 13;19(2):248-57. doi: 10.1038/sj.onc.1203306.

Abstract

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is specifically expressed by transformed human keratinocytes in squamous cell carcinomas in vivo and its expression correlates with their invasion capacity. Here, we show, that interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of A-5 cells through type I collagen. IFN-gamma also rapidly and transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is associated with marked reduction in MMP-13 expression. These observations identify a novel role for IFN-gamma as a potent inhibitor of collagenolytic activity and invasion of transformed squamous epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma involves activation of ERK1,2 and STAT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / metabolism*
  • Collagenases / biosynthesis*
  • Collagenases / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interferon-gamma / pharmacology*
  • Keratinocytes / drug effects
  • Keratinocytes / enzymology*
  • Keratinocytes / metabolism
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / biosynthesis*
  • Matrix Metalloproteinases / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Organ Specificity / genetics
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • Trans-Activators / metabolism*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases