Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma

Int J Oncol. 2008 Jun;32(6):1253-61. doi: 10.3892/ijo_32_6_1253.

Abstract

Although mutations of APC, CTNNB1 (beta-catenin) and AXIN1 are rare in oral squamous cell carcinoma (OSCC), activation of the Wnt signaling pathway is thought to play an important role in oral carcinogenesis. In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. We frequently detected loss of membrane localization of beta-catenin and its cytoplasmic or nuclear accumulation in OSCC cell lines, although these cell lines showed no APC or CTNNB1 (beta-catenin) mutations and no methylation of CDH1 (E-cadherin). By contrast, we frequently detected methylation of SFRP1 (7/17, 41%) SFRP2 (16/17, 94%) and SFRP5 (14/17, 82%) in a panel of OSCC cell lines, as well as in specimens of primary tumors collected from 44 OSCC patients (SFRP1, 10/42, 24%; SFRP2, 16/44, 36%; SFRP5, 7/43, 16%). We also observed that OSCC cell lines express various Wnt ligands, and that ectopic expression of SFRPs inhibited cancer cell proliferation. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Aged
  • Antigens, CD
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Middle Aged
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / metabolism
  • Mutation
  • Wnt Proteins
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Antigens, CD
  • CDH1 protein, human
  • CTNNB1 protein, human
  • Cadherins
  • Eye Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SFRP1 protein, human
  • SFRP2 protein, human
  • SFRP5 protein, human
  • Wnt Proteins
  • beta Catenin