Differential regulation of MMP-9 and TIMP-2 expression in malignant melanoma developed in metallothionein/RET transgenic mice

Jpn J Cancer Res. 1999 Jan;90(1):86-92. doi: 10.1111/j.1349-7006.1999.tb00670.x.


We recently established a metallothionein-I(MT)/RET transgenic mouse line in which skin melanosis, benign melanocytic tumor and malignant melanoma develop stepwise. Malignant melanoma cells but not benign melanocytic tumor cells had metastatic ability in transgenic mice. In the present study, we investigated the expression of several matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MT1-MMP, TIMP-1 and TIMP-2, in these tumors. Western and northern blot analyses revealed that malignant transformation of melanocytic tumors developed in MT/RET transgenic mice accompanied with upregulation of MMP-9 and downregulation of TIMP-2. Expression of other MMP and TIMP genes examined was very low or undetectable in both benign and malignant tumors. Since activation of MMP-9 in malignant tumors was detected by gelatin zymography, these results suggest that imbalance of expression of the MMP-9 and TIMP-2 genes might be associated with metastatic ability of melanoma cells developed in MT/RET transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Collagenases / genetics*
  • Drosophila Proteins*
  • Gelatinases / genetics*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic*
  • In Situ Hybridization
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Melanocytes / enzymology
  • Melanocytes / pathology
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Metalloendopeptidases / genetics*
  • Metallothionein / genetics*
  • Metallothionein / metabolism
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogenes*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Recombinant Proteins / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*


  • Drosophila Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Metallothionein
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9