Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation.

Abstract

PURPOSE:

In this study, we examined the promoter methylation status and expression of 14-3-3 sigma and evaluated its clinical significance in epithelial ovarian cancer.

EXPERIMENTAL DESIGN:

Twelve ovarian cancer cell lines; 2 ovarian surface epithelial cell lines; and 8 normal, 8 benign, 12 borderline, and 102 ovarian cancer tissues were examined. Methylation-specific PCR, quantitative reverse transcription-PCR, and immunohistochemistry were used to evaluate methylation status and expression of 14-3-3 sigma gene and protein.

RESULTS:

Among the 12 ovarian cancer cell lines, the presence of a methylated band was detected in seven cell lines. Median values of relative 14-3-3 sigma gene expression in cancers with methylation (3.27) were significantly lower than those without methylation (16.4; P < 0.001). Treatment of 5-aza-2'-deoxycitidine resulted in the demethylation of the promoter CpG islands and reexpression. All of the normal, benign, and borderline tissues were positive for 14-3-3 sigma protein, and in ovarian cancer tissues, 73.5% (75 of 102) were positive for 14-3-3 sigma protein and was almost consistent with methylation status. Negative immunoreactivity of 14-3-3 sigma was significantly correlated with high age and serous histology, high-grade, advanced-stage residual tumor of >2 cm, high serum CA125, high Ki-67 labeling index, and positive p53 immunoreactivity. 14-3-3 sigma immunoreactivity was significantly associated with overall survival (P = 0.0058).

CONCLUSIONS:

Our findings suggest that 14-3-3 sigma is inactivated mainly by aberrant DNA methylation and that it may play an important role in the pathogenesis of epithelial ovarian cancer.

• Authors: Jun-ichi Akahira, Youko Sugihashi, Takashi Suzuki, Kiyoshi Ito, Hitoshi Niikura, Takuya Moriya, Makoto Nitta, Hitoshi Okamura, Satoshi Inoue, Hironobu Sasano, Kunihiro Okamura, Nobuo Yaegashi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 8 Pg. 2687-93 (Apr 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15102672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Biomarkers, Tumor
• DNA, Complementary
• Neoplasm Proteins
• Exonucleases
• Exoribonucleases
• SFN protein, human

Topics

• 14-3-3 Proteins
• Adult
• Aged
• Biomarkers, Tumor (biosynthesis)
• Cell Line, Tumor
• CpG Islands
• DNA Methylation
• DNA, Complementary (metabolism)
• Disease Progression
• Epithelial Cells (metabolism)
• Exonucleases (biosynthesis)
• Exoribonucleases
• Female
• Gene Library
• Humans
• Immunohistochemistry
• Middle Aged
• Neoplasm Proteins (biosynthesis)
• Ovarian Neoplasms (metabolism, pathology)
• Polymerase Chain Reaction
• Promoter Regions, Genetic
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors