Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma
Journal
Molecular Cancer
Journal Volume
8
Pages
120
Date Issued
2009
Author(s)
Abstract
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. ? 2009 Torng et al; licensee BioMed Central Ltd.
SDGs
Other Subjects
5 aza 2' deoxycytidine; complementary DNA; pifithrin alpha; protein p53; somatomedin binding protein 3; protein p53; somatomedin binding protein 3; adult; article; cancer cell culture; cancer growth; cancer survival; carcinogenesis; controlled study; endometrioid carcinoma; expression vector; female; gene expression; genetic transfection; human; human cell; immunohistochemistry; major clinical study; methylation; mutagenesis; ovary carcinoma; promoter region; regulatory mechanism; reverse transcription polymerase chain reaction; transcription initiation site; Western blotting; wild type; DNA methylation; endometrioid carcinoma; gene expression regulation; genetic transcription; genetics; middle aged; ovary tumor; promoter region; survival rate; Adult; Carcinoma, Endometrioid; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Insulin-Like Growth Factor Binding Protein 3; Middle Aged; Ovarian Neoplasms; Promoter Regions, Genetic; Survival Rate; Transcription, Genetic; Tumor Suppressor Protein p53
Type
journal article