Silencing of tissue factor pathway inhibitor-2 gene in malignant melanomas

Int J Cancer. 2007 Jul 15;121(2):301-7. doi: 10.1002/ijc.22637.


To identify tumor-suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV-I, MeWo and WM-115. Seventy-nine known genes with CGIs were identified as being upregulated (>or=16-fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI-2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5-aza-dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI-2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) (p=0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI-2. The results showed that TFPI-2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • CpG Islands
  • DNA Methylation / drug effects
  • Decitabine
  • Gene Expression Regulation / radiation effects
  • Gene Silencing*
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Humans
  • Immunohistochemistry
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ultraviolet Rays


  • Glycoproteins
  • tissue-factor-pathway inhibitor 2
  • Decitabine
  • Azacitidine