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Expression and functional analysis of the WAP four disulfide core domain 1 gene in human melanoma

Suhu Liu1, Paul Howell, Suping Ren

  • 1Dana-Farber Cancer Institute, Boston, MA 02115, USA. suhu_liu@dfci.harvard.edu

Clinical & Experimental Metastasis
|June 3, 2009
PubMed

Insights

WFDC1 gene expression is reduced in melanoma. Overexpressing WFDC1 suppressed tumor growth in mice, potentially by increasing Dickkopf-1 (Dkk1) and inhibiting Wnt signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Melanoma tumorigenesis mechanisms are not fully understood.
  • WFDC1 is frequently down-regulated in melanoma.
  • WFDC1 expression is lost in 80% of melanoma samples.

Purpose of the Study:

  • To investigate the role of WFDC1 in melanoma.
  • To elucidate the mechanisms of WFDC1 down-regulation.
  • To evaluate the therapeutic potential of WFDC1.

Main Methods:

  • Gene expression profiling of normal human epidermal melanocytes (NHEM) and melanoma samples.
  • Analysis of WFDC1 promoter methylation.
  • Overexpression of WFDC1 in melanoma cell lines (A375, LOX) and assessment in a murine xenograft model.
  • Gene expression microarray analysis to identify downstream targets.

Main Results:

  • WFDC1 expression is significantly reduced or lost in most melanoma cell lines and tissues.
  • Promoter hypermethylation causes WFDC1 silencing in 20% of melanoma cell lines.
  • WFDC1 overexpression delayed tumor growth in vivo, but not in vitro.
  • WFDC1 overexpression led to increased Dickkopf-1 (Dkk1) gene expression.

Conclusions:

  • WFDC1 acts as a tumor suppressor in melanoma.
  • WFDC1 silencing via promoter hypermethylation is a mechanism in melanoma.
  • WFDC1's tumor suppressive function may involve up-regulation of Dkk1, inhibiting Wnt signaling.

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