High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A

Cancer Cell. 2011 May 17;19(5):601-12. doi: 10.1016/j.ccr.2011.03.010.

Abstract

Wnt canonical signaling is critical for normal development as well as homeostasis of several epithelial tissues, and constitutive activation of this pathway is commonly observed in carcinomas. We show here that 50% of human sarcomas (n = 45) and 65% of sarcoma cell lines (n = 23) of diverse histological subtypes exhibit upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, we identify alterations including overexpression or gene amplification of Wnt ligands and/or LRP5/6 coreceptors and epigenetic silencing of different cell surface Wnt antagonists. Mutations in adenomatous polyposis coli (APC) gene were observed in two nonautocrine Wnt-positive sarcoma cell lines. Finally, downregulation of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the downregulation of CDC25A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autocrine Communication
  • Cell Line, Tumor
  • Cell Proliferation*
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genes, APC
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Mutation
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Sarcoma / genetics
  • Sarcoma / metabolism*
  • Sarcoma / pathology
  • Signal Transduction*
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism*
  • Time Factors
  • Transfection
  • Tumor Burden
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism*

Substances

  • CTNNB1 protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • TCF Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • CDC25A protein, human
  • cdc25 Phosphatases