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Background  Insulin-like growth factor binding protein (IGFBP-3) is an antiproliferative, pro-apoptotic and invasion suppressor protein which is transcriptionally regulated by p53. Promoter methylation has been linked to gene silencing and cancer progression. We studied the correlation between IGFBP-3 and p53 expression as well as  IGFBP-3  promoter methylation in ovarian endometrioid carcinoma (OEC) by immunohistochemical staining and quantitative methylation-specific PCR (qMSP). Additionally, we assessed the molecular regulatory mechanism of wild type (wt) p53 on IGFBP-3 expression using two subclones of OEC, the OVTW59-P0 (low invasive) and P4 (high invasive) sublines.    Results  In 60 cases of OEC, 40.0% showed lower IGFBP-3 expression which was significantly correlated with higher  IGFBP-3  promoter methylation. p53 overexpression was detected in 35.0% of OEC and was unrelated to clinical outcomes and IGFBP-3. By Kaplan-Meier analysis, patients with lower IGFBP-3, higher  IGFBP-3  promoter methylation, and normal p53 were associated most significantly with lower survival rates. In OEC cell line, IGFBP-3 expression was correlated with  IGFBP-3  promoter methylation. IGFBP-3 expression was restored after treatment with a DNA methy-transferase inhibitors (5-aza-deoxycytidine) and suppressed by a p53 inhibitor (pifithrin-α). The putative p53 regulatory sites on the promoter of  IGFBP-3  were identified at -210, -206, -183 and -179 bases upstream of the transcription start site. Directed mutagenesis at these sites quantitatively reduced the transcription activity of IGFBP-3.    Conclusion  Our data suggests that IGFBP-3 silencing through  IGFBP-3  promoter methylation in the absence of p53 overexpression is associated with cancer progression. These results support a potential role of  IGFBP-3  methylation in the carcinogenesis of OEC.

Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma