Epigenetic Changes Of Oncogenic And Anti-Oncogenic Factors Encoding Gene During Gynaecological Tumour Progression

Hypoxia is known to play key roles in the development and progression of tumours. We previously demonstrated that breast cancer type 1 susceptibility protein (BRCA1) and S100 calcium-binding protein A4 (S100A4), critical molecules for tumour initiation and metastasis, were differential expressed in ovarian cancer. Therefore, we examined the mechanisms of the BRCA1 and S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of BRCA1 and S100A4 were found to correlate with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the expression of BRCA1 and S100A4 gene was associated with epigenetic changes in the regulatory regions of BRCA1 and S100A4 cording genes in ovarian carcinoma cell and tissues. The expression of S100A4 was increased under hypoxia, and then was associated with elevated invasiveness. In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the enhancing binding activity of hypoxia inducible factor-1 (HIF-1 to a methylation -free HRE in ovarian carcinoma cells. These findings indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 over expression and the epigenetic transformation of ovarian carcinoma cells into the ''metastatic phenotype''.