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

Item Type:Article
Title:The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor (TCF) signaling in colon cancer
Creators Name:Stein, U. and Arlt, F. and Walther, W. and Smith, J. and Waldman, T. and Harris, E.D. and Mertins, S.D. and Heizmann, C.W. and Allard, D. and Birchmeier, W. and Schlag, P.M. and Shoemaker, R.H.
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 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.
Keywords:Cell Movement, Colonic Neoplasms, Gene Expression Regulation, HCT116 Cells, Neoplasm Invasiveness, Neoplasm Metastasis, Messenger RNA, S100 Proteins, Signal Transduction, TCF Transcription Factors, Beta Catenin
Source:Gastroenterology
ISSN:0016-5085
Publisher:Elsevier (The Netherlands)
Volume:131
Number:5
Page Range:1486-1500
Date:November 2006
Official Publication:https://doi.org/10.1053/j.gastro.2006.08.041
PubMed:View item in PubMed

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