(1)卵巣癌の発生・進展の過程でエピジェネティックに抑制されている遺伝子の検索(講演要旨,<特集>第60回学術講演会シンポジウム3「婦人科腫瘍とエピジェネティクス-臨床へのトランスレーション-」)

NDLデジタルコレクション 参考文献19件

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  • Investigation of Epigenetically Inactivated Genes in the Process of Tumorigenesis and Progression in Epithelial Ovarian Cancer

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DNA methylation has an essential regulatory function in mammalian development, suppressing gene activity by changing chromatin structure. It has become apparent that aberrant DNA methylation of promoter region CpG islands may serve as an alternate mechanism to genetic defects in the inactivation of tumor suppressor genes in human cancers. Accordingly, the identification of gene targets of methylation-associated silencing could lead to novel genes involved in the initiation and progression of human neoplasia. CpG island methylator phenotype (CIMP) is reported to be associated with distinct clinical and molecular features in many cancers. In the present study, we examined whether the CIMP is associated with clinicopathological parameters in epithelial ovarian cancer. We also studied the expression and methylation status of 14-3-3sigma (σ), cyclinD2, and estrogen receptor β (ERβ) genes in detail. In total, 8 ovarian surface epithelial cells (OSEs), 12 ovarian cancer cell lines, and 130 normal to ovarian cancer tissues were examined. Fifteen genes (ERβ, DAPK, cyclin D2, RARβ, p16, RASSF1A, CHFR3, 14-3-3σ, TMS1, BMP2, RIZ1, WIF-1, SFRP1, SFRP2, SFRP5) were examined by methylation specific PCR (MSP) and bisulfate sequence. The expression of mRNAs was examined by real-time RT-PCR. The expression of 14-3-3s protein was examined by immunohistochemistry. The research protocol was approved by the ethics committee of Tohoku University Graduate School of Medicine, Sendai, Japan. The number of genes methylated in cancerous tissue (2.95) was significantly higher than that of normal tissues (1.5) (p<0.05). Clustering analyses revealed that the methylation was more frequent in clear cell histology but was not associated with prognosis. The 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). In ovarian cancer tissues, 73.5% (75/102) and 36.3% (37/102) were positive for 14-3-3σ and decreased expression was significantly associated with poor prognosis. Aberrant methylation of Cyclin D2 was present in 5/12 ovarian cancer cell lines. In ovarian cancer tissues, methylation bands were detected in 16/71 cases and the methylation status was significantly associated with poor prognosis. With regard to ERβ, the expression of exon ON, ERβ1, β2, β4 mRNA was significantly lower in ovarian cancer cell lines and tissues than normal counterpart. Significant correlation between promoter ON hypermethylation and loss of exon ON, ERβ1, β2, and β4 mRNA expression was observed in ovarian cancer cells and tissues. In conclusion, aberrant CpG island methylation is an epigenetic change that is largely responsible for silencing of tumor suppressor genes in epithelial ovarian cancer.

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