Epigenetic changes within the promoter region of the HLA-G gene in ovarian tumors

A region containing an intact hypoxia response element (HRE) remained completely methylated in the cell line after treatment with 5-aza-dC and was completely methylated in all of the ovarian tumor (malignant and benign) samples examined, but only variably methylated in normal OSE samples. HLA-G expression was significantly increased in the 5-aza-dC treated cell line but no significant difference was detected between the tumor and OSE samples examined.Since HRE is the binding site of a known repressor of HLA-G expression (HIF-1), we hypothesize that methylation of the region surrounding the HRE may help maintain the potential for expression of HLA-G in ovarian tumors. The fact that no correlation exists between methylation and HLA-G gene expression between ovarian tumor samples and OSE, suggests that changes in methylation may be necessary but not sufficient for HLA-G expression in ovarian cancer.Classic and non-classic HLA (human leukocyte antigen) class I genes play a central role in the regulation of the immune response. The non-classic HLA-G gene is expressed in a variety of tissues but perhaps most notably in the fetal-maternal interface on the extravillous cytotrophoblast and has been postulated to help protect the fetus from maternal allorecognition [1]. This hypothesis is supported by subsequent studies demonstrating that HLA-G proteins can suppress a variety of immune functions including natural killer (NK) cell-mediated cytolysis and the T-cell proliferative response [2,3]. Recent findings indicate that HLA-G antigens are present in ovarian and various other types of malignant cells and tissues [4-7]. These findings and others have led to the hypothesis that induction of HLA-G expression in tumor cells may contribute to their avoidance of immunosurveillance by the host [8,9] (but disputed by [10]).Sequences known to be involved in the transcriptional regulation of most HLA class I genes are disrupted in the HLA-G gene raising questions as to the mechanisms