Abstract
BackgroundThis study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA).Materials and methodsThe promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis.ResultsFrequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts. The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed.ConclusionsMethylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway.
Highlights
Ovarian clear cell adenocarcinoma (OCCA) is recognized as a distinct histological type of cancer, and its frequency among epithelial ovarian cancers is estimated to be less than 10% [1,2]
Methylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in ovarian clear cell adenocarcinoma (OCCA) patients
Patients with stage III and IV OCCA exhibited a 54% (13/24) high rate of platinum resistance or refractory
Summary
Ovarian clear cell adenocarcinoma (OCCA) is recognized as a distinct histological type of cancer, and its frequency among epithelial ovarian cancers is estimated to be less than 10% [1,2]. Higher p21 and cyclin E with lower TP53 and cyclin A levels were detected in OCCA compared to other epithelium ovarian cancers, and they are thought to be involved in the carcinogenesis of OCCA [7]. Silencing of Wilms tumor suppressor 1 sense and antisense genes by promoter methylation in OCCA revealed the epigenetic involvement of OCCA in carcinogenesis as distinguished from ovarian serous adenocarcinoma [8]. Mutations at PPP2R1A and ARID1A were found, and it was suggested that aberrant chromatin remodeling may contribute to the pathogenesis of OCCA, indicating that epigenetic changes in cancer cells may occur through specific modifications of chromatin proteins [13]. This study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA)
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