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Wnt pathway inhibitors are strongly down-regulated in pituitary tumors

Marianne S Elston1, Anthony J Gill, John V Conaglen

  • 1Cancer Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. marianne@med.usyd.edu.au

Endocrinology
|December 15, 2007
PubMed

Insights

Wnt inhibitory factor-1 (WIF1) is downregulated in pituitary tumors, potentially acting as a tumor suppressor, particularly in nonfunctioning types. Wnt pathways play a role in pituitary tumor development.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • The origins of sporadic pituitary tumors remain unknown.
  • Wnt signaling pathways are implicated in various human cancers, but their role in pituitary tumors is not well understood.

Purpose of the Study:

  • To investigate the role of Wnt pathway inhibitors, specifically secreted frizzled-related proteins (sFRPs), in the pathogenesis of pituitary tumors.
  • To determine the expression levels and potential epigenetic regulation of Wnt inhibitory factor-1 (WIF1) in pituitary tumors.

Main Methods:

  • Microarray analysis to identify differentially expressed sFRPs in pituitary tumors.
  • Real-time quantitative RT-PCR to confirm mRNA expression of WIF1, sFRP2, and sFRP4.
  • Analysis of WIF1 promoter methylation and WIF1 protein expression via immunohistochemistry.
  • Western blotting and RT-PCR to assess Wnt pathway target gene cyclin D1 expression.
  • In vitro studies transfecting GH3 cells with WIF1 to evaluate its effect on cell proliferation.

Main Results:

  • Four sFRP family members were differentially expressed in pituitary tumors compared to normal pituitary tissue.
  • Reduced mRNA expression of WIF1, sFRP2, and sFRP4 was confirmed in all pituitary tumor subtypes.
  • Hypermethylation of the WIF1 promoter was observed in 88% of pituitary tumors, correlating with absent or weak WIF1 protein staining.
  • Cyclin D1, a Wnt pathway target gene, was upregulated in nonfunctioning pituitary tumors.
  • WIF1 transfection in GH3 cells led to decreased cell proliferation and colony formation.

Conclusions:

  • Wnt inhibitory factor-1 (WIF1) may function as a tumor suppressor, especially in nonfunctioning pituitary tumors.
  • The Wnt signaling pathway appears to be involved in pituitary tumorigenesis.
  • Epigenetic silencing of WIF1 through promoter hypermethylation is a significant mechanism in pituitary tumor development.

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