Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma
1 Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan
2 Department of Medical Research, Sijhih Cathay General Hospital, New Taipei City, Taiwan
3 School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan
4 Department of Obstetrics and Gynecology, School of Medicine, Taipei Medical University, Taipei, Taiwan
5 Department of Pathology, Sijhih Cathay General Hospital, New Taipei City, Taiwan
6 Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, Taipei, Taiwan
7 Graduate Institute of Oncology, Graduate Institute of Clinical Medicine, Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
Molecular Cancer 2012, 11:53 doi:10.1186/1476-4598-11-53Published: 8 August 2012
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).
Materials and methods
The 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.
Frequencies 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.
Methylation 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.