Clinicopathological Significance and Prognostic Value of DNA Methyltransferase 1, 3a, and 3b Expressions in Sporadic Epithelial Ovarian Cancer

Xuefeng Bai,Enhua Wang,Yingzi Fu,Desheng Huang,Haishan Zhao,Zhiguo Song,Zhaojin Yu,Lin Zhao,Weifan Yao,Minjie Wei,Xiaoyi Mi,Zhihong Zheng,M.Carolina Elias

doi:10.1371/journal.pone.0040024

Abstract

Altered DNA methylation of tumor suppressor gene promoters plays a role in human carcinogenesis and DNA methyltransferases (DNMTs) are responsible for it. This study aimed to determine aberrant expression of DNMT1, DNMT3a, and DNMT3b in benign and malignant ovarian tumor tissues for their association with clinicopathological significance and prognostic value. A total of 142 ovarian cancers and 44 benign ovarian tumors were recruited for immunohistochemical analysis of their expression. The data showed that expression of DNMT1, DNMT3a, and DNMT3b was observed in 76 (53.5%), 92 (64.8%) and 79 (55.6%) of 142 cases of ovarian cancer tissues, respectively. Of the serious tumors, DNMT3a protein expression was significantly higher than that in benign tumor samples (P = 0.001); DNMT3b was marginally significant down regulated in ovarian cancers compared to that of the benign tumors (P = 0.054); DNMT1 expression has no statistical difference between ovarian cancers and benign tumor tissues (P = 0.837). Of the mucious tumors, the expression of DNMT3a, DNMT3b, and DNMT1 was not different between malignant and benign tumors. Moreover, DNMT1 expression was associated with DNMT3b expression (P = 0.020, r = 0.195). DNMT1 expression was associated with age of the patients, menopause status, and tumor localization, while DNMT3a expression was associated with histological types and serum CA125 levels and DNMT3b expression was associated with lymph node metastasis. In addition, patients with DNMT1 or DNMT3b expression had a trend of better survival than those with negative expression. Co-expression of DNMT1 and DNMT3b was significantly associated with better overall survival (P = 0.014). The data from this study provided the first evidence for differential expression of DNMTs proteins in ovarian cancer tissues and their associations with clinicopathological and survival data in sporadic ovarian cancer patients.

Highlights

Epigenetic alteration of the genomic DNA refers to functionally relevant modifications of the genome that affects gene expression but do not involve a change in the nucleotide sequence, which plays an important role in human carcinogenesis
We for the first time immunohistochemically determined the expression of DNMT1, DNMT3a, and DNMT3b proteins in benign and malignant ovarian tumor tissues
The data showed that DNMT3a expression was higher in ovarian cancer than that in benign tumors, which was consistent with the previous studies in other types of cancer [15,37,38]

Summary

Introduction

Epigenetic alteration of the genomic DNA refers to functionally relevant modifications of the genome that affects gene expression but do not involve a change in the nucleotide sequence, which plays an important role in human carcinogenesis. The preferred target of DNMT1 is hemi-methylated DNA [4,5] and this protein functions as a ‘‘maintenance’’ methyltransferase and the primary enzyme responsible for copying methylation patterns after DNA replication It localizes to replication foci and interacts with proliferation cell nuclear antigen (PCNA) [6]. DNMT3a and DNMT3b are essential for early embryonic development and responsible for de novo methylation [7] Overexpression of these three DNMTs has been reported in various malignancies and associated with poor survival of different cancers, including lung, liver, and cervical cancers and lymphomas [8,9,10,11,12,13,14,15,16,17,18]. Antisense oligonucleotides targeting DNMT genes, for example MG98, appear to be effective in preclinical studies and has entered into clinical phase I and phase II studies [20,21]

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