Metastasis is the most relevant prognostic factor in cancer. S100A4 (metastasin) is one of the genes which plays a critical role in the process of colon cancer metastasis. Now, Ulrike Stein (laboratory of Peter Schlag) and co-workers from the Surgical Oncology Department of the Charité and the MDC in close cooperation with the National Cancer Institute, USA, and others describe the metastasis-associated gene S100A4 as a novel target of the β -catenin/TCF signaling pathway (Gastroenterology 131( 5) pp.1486-1500). S100A4 was identified as the most regulated gene by gain-of-function β -catenin using a 10K microarray. Cell lines with mutant b -catenin expressed up to 60-fold elevated S100A4 levels, displayed strongly increased migration and invasion in vitro, and induced metastasis in mice, compared with wild-type β -catenin harboring cells. S100A4 siRNA, β -catenin siRNA, or dnTCF knocked down S100A4 and blocked these biological effects. S100A4 cDNA transfection increased migration and invasion. Furthermore, a TCF binding site within the S100A4 promoter was identified and the direct binding of heterodimeric β -catenin/TCF complexes to the S100A4 promoter was demonstrated. Reporter assays confirmed the β -catenin-induced S100A4 promoter activity. Patient colon tumors heterozygous for gain-of-function β -catenin showed concomitant nuclear β -catenin localization, high S100A4 expression, and metastases. S100A4 mRNA expression was increased in those primary colon cancers, which later developed distant metastases, compared to tumors which did not metastasize. In summary, S100A4 is a direct β -catenin/TCF target, and has prognostic value for metastasis formation in colon cancer patients. Thus, S100A4 represents an important tool for diagnostics and a promising target for new therapeutic intervention.
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