Increased expression of the invasion- and metastasis-associated protein S100A4 is found in many types of cancer, but the regulation of S100A4 expression is poorly understood. The microenvironment surrounding tumors has a significant effect on tumor progression, and in the present study, we investigated the role of the microenvironment in the expression of S100A4. Tumors of three different human carcinoma cell lines were established in the tongue or skin of mice, and S100A4 expression was assessed by quantitative RT-PCR, Western blotting, and immunohistochemical analysis in tumors and stromal tissue and in cancer cells grown in vitro. Tongue tumors of the oral squamous cell carcinoma cell line HSC-4 showed a pronounced increase in S100A4 expression during tumor growth, whereas only a minor increase was detected in skin tumors of the same cell line. The S100A4 expression correlated with the methylation status of cytosine-guanine sites in the first intron of the gene. For all cell lines, S100A4 expression in the tumor stroma was related to the presence of inflammatory cells rather than to the level of S100A4 in the tumor cells.
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