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Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia\u2010response elements (HRE) of the S100A4 gene in a time\u2010dependent fashion, in association with the increased binding of HIF\u20101\u03b1 to a methylation\u2010free HRE in ovarian carcinoma cells. These results indicate that hypoxia\u2010induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the \u201cmetastatic phenotype.\u201d<\/jats:p>","DOI":"10.1002\/ijc.27448","type":"journal-article","created":{"date-parts":[[2012,1,27]],"date-time":"2012-01-27T12:28:42Z","timestamp":1327667322000},"page":"1755-1767","source":"Crossref","is-referenced-by-count":61,"title":["Hypoxia upregulates ovarian cancer invasiveness <i>via<\/i> the binding of HIF\u20101\u03b1 to a hypoxia\u2010induced, methylation\u2010free hypoxia response element of S100A4 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