Downregulation of WIF-1 by hypermethylation in astrocytomas

Acta Biochim Biophys Sin (Shanghai). 2010 Jun 15;42(6):418-25. doi: 10.1093/abbs/gmq037.


Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression of WIF-1 activate Wnt signaling aberrantly and induce the development of several human tumors. By using RT-PCR, immunohistochemistry and methylation-specific PCR, we analyzed the expression and methylation of WIF-1 in 4 normal brain tissues, 35 freshly resected astrocytoma tissues and 4 glioblastoma-derived cell lines. Significant downregulation of WIF-1 mRNA and protein expression levels was observed in astrocytoma tissues compared with normal brain tissues. Significant association between WIF-1 downregulation and pathological grade of astrocytomas was found. WIF-1 gene aberrant methylation was observed in 19 of 35 (54.29%) tumor samples. The promoter methylation tumors showed low WIF-1 protein and mRNA expression, whereas the promoter unmethylation tumors displayed high protein and mRNA expression levels. Moreover, complete absence of WIF-1 mRNA expression was observed in four cell lines, whereas treatment with demethylating agent, 5-aza-2'-deoxycytidine, restored WIF-1 expression. Our results suggested that the WIF-1 gene is frequently silenced in astrocytoma by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Astrocytoma / genetics*
  • Azacitidine / analogs & derivatives
  • Azacitidine / metabolism
  • Cell Line, Tumor
  • DNA Methylation*
  • Decitabine
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Wnt Proteins / genetics
  • beta Catenin / genetics


  • Adaptor Proteins, Signal Transducing
  • RNA, Messenger
  • Repressor Proteins
  • WIF1 protein, human
  • Wnt Proteins
  • beta Catenin
  • Decitabine
  • Azacitidine