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

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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., Arlt, F., Walther, W., Smith, J., Waldman, T., Harris, E.D., Mertins, S.D., Heizmann, C.W., Allard, D., Birchmeier, W., 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 / Saunders
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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