Decreased expression of 14-3-3σ is associated with advanced disease in human epithelial ovarian cancer:: Its correlation with aberrant DNA methylation
Decreased expression of 14-3-3σ is associated with advanced disease in human epithelial ovarian cancer:: Its correlation with aberrant DNA methylation
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DOI：
10.1158/1078-0432.ccr-03-0510
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发表时间：
2004-04-15
影响因子：
11.5
通讯作者：
Yaegashi, N
中科院分区：
文献类型：
--
作者：
Akahira, J;Sugihashi, Y;Yaegashi, N
目的：在本研究中，我们检测14-3-3sigma启动子甲基化状态和表达，并评估其在上皮性卵巢癌中的临床意义。实验设计：12株卵巢癌细胞系；2个卵巢表面上皮细胞系；正常8例，良性8例，交界性12例，102例。采用甲基化特异性PCR、定量逆转录PCR和免疫组化检测14-3-3sigma基因和蛋白的甲基化状态和表达。结果：在12个卵巢癌细胞系中，在7个细胞系中检测到甲基化条带的存在。有甲基化的肿瘤中14-3-3sigma基因相对表达的中位数（3.27）显著低于无甲基化的肿瘤中位数（16.4,P < 0.001）。5-叠氮-2'-脱氧胞苷处理导致启动子CpG岛的去甲基化和再表达。所有正常、良性和交界性组织中14-3-3 sigma蛋白均呈阳性，而在卵巢癌组织中，73.5%（102例中的75例）的14-3-3 sigma蛋白呈阳性，与甲基化状态基本一致。14-3-3 sigma阴性免疫反应性与高年龄、高浆液组织学、高级别、晚期肿瘤残留bbb2cm、高血清CA125、高Ki-67标记指数、p53阳性免疫反应性显著相关。14-3-3sigma免疫反应性与总生存率显著相关（P = 0.0058）。结论：14-3-3 - sigma主要通过DNA甲基化异常失活，可能在上皮性卵巢癌的发病机制中发挥重要作用。
Purpose: In this study, we examined the promoter methylation status and expression of 14-3-3sigma 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 14-3-3sigma 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 14-3-3sigma 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. 14-3-3sigma immunoreactivity was significantly associated with overall survival (P = 0.0058).Conclusions: Our findings suggest that 14-3-3sigma is inactivated mainly by aberrant DNA methylation and that it may play an important role in the pathogenesis of epithelial ovarian cancer.