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

  1. Author:
    Stein, U.
    Arlt, F.
    Walther, W.
    Smith, J.
    Waldman, T.
    Harris, E. D.
    Mertins, S. D.
    Heizmann, C. W.
    Allard, D.
    Birchmeier, W.
    Schlag, P. M.
    Shoemaker, R. H.

  2. Author Address

    Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. Robert Rossle Canc Hosp, Dept Surg & Surg Oncol, Berlin, Germany. Georgetown Univ, Sch Med, Vincent T Lombardi Canc Res Ctr, Washington, DC USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Frederick, MD 21701 USA. SAIC, Frederick, MD USA. Univ Zurich, Div Clin Chem & Biochem, Dept Pediat, Zurich, Switzerland. Univ Liverpool, Canc & Polio Fund Labs, Liverpool L69 3BX, Merseyside, England.;Stein, U, Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13092 Berlin, Germany.;ustein@mdc-berlin.de
    1. Year: 2006
    2. Date: Nov
  2. Journal: Gastroenterology
    1. 131
    2. 5
    3. Pages: 1486-1500
  4. Type of Article: Article
  5. ISSN: 0016-5085
  1. Abstract:

    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 hererozygous 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 rnetastasis 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-cateninnin/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.

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External Sources

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  2. DOI: 10.1053/j.gastro.2006.08.041
  3. View record in Web of Science®
  4. WOS: 000242221000020

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