The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer

Gastroenterology. 2006 Nov;131(5):1486-500. doi: 10.1053/j.gastro.2006.08.041. Epub 2006 Aug 22.


Background & aims: Activation of the Wnt/beta-catenin pathway is frequently observed in colorectal cancers. Our aim was to elucidate the impact of gain-of-function beta-catenin on the metastasis-associated gene S100A4 in human colon cancer cell lines and tumors.

Methods: We analyzed cell lines heterozygous for gain-of-function and wild-type beta-catenin, and variants homozygous for gain- or loss-of-function mutation in beta-catenin, for S100A4 expression, cell motility, and in vivo metastasis. beta-catenin-mediated S100A4 promoter activation was tested by reporter assays. For human colon carcinomas, S100A4 expression, beta-catenin genotype, and metachronous metastasis were correlated.

Results: We identified S100A4 as the most regulated gene by gain-of-function beta-catenin using a 10K microarray. Cell lines with gain-of-function beta-catenin expressed up to 60-fold elevated S100A4 levels, displayed strongly increased migration and invasion in vitro, and induced metastasis in mice. S100A4 small interfering RNA, beta-catenin small interfering RNA, or dominant negative T-cell factor (TCF) knocked down S100A4 and blocked biological effects. S100A4 complementary DNA transfection increased migration and invasion. We identified a TCF binding site within the S100A4 promoter and demonstrated the direct binding of heterodimeric beta-catenin/TCF complexes. Reporter assays confirmed the beta-catenin-induced S100A4 promoter activity. Furthermore, S100A4 mRNA expression was increased in primary colon cancers, which later developed distant metastases, compared to non-metastasizing tumors. Colon tumors heterozygous for gain-of-function beta-catenin showed concomitant nuclear beta-catenin localization, high S100A4 expression, and metastases.

Conclusions: S100A4 is a direct beta-catenin/TCF target, induces migration and invasion in vitro and metastasis in vivo, and has value for prognosis of metastasis formation in colon cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement
  • Colonic Neoplasms / pathology*
  • Gene Expression Regulation
  • HCT116 Cells
  • Humans
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA, Messenger / analysis
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / genetics*
  • Signal Transduction / physiology*
  • TCF Transcription Factors / physiology*
  • beta Catenin / genetics
  • beta Catenin / physiology*


  • RNA, Messenger
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • TCF Transcription Factors
  • beta Catenin
  • S100A4 protein, human