Background: Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated. Methods: In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. Results: Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival. Conclusions: Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.
背景：尽管上皮性卵巢癌（EOC）的治疗近期有所进展，但其复发率和死亡率并未显著改善。DNA高甲基化通常与不良预后和化疗耐药相关，但DNA甲基转移酶（DNMTs）在EOC中的作用仍有待研究。方法：本研究系统检索了EOC患者的基因表达数据，并对108例原发性和26例复发性肿瘤中DNMTs的免疫组化表达进行了分析。结果：结果显示，与非肿瘤组织相比，肿瘤组织中DNMT1、DNMT3A、DNMT3B和DNMT3L的RNA水平较高，而DNMT2水平较低；且从II期到IV期癌组织中，DNMT3A和DNMT2的表达逐渐降低。蛋白质组学数据也提示肿瘤组织中DNMT1和DNMT3A水平升高。同样，与非肿瘤组织和低级别肿瘤相比，高级别癌组织中DNMT1、DNMT3A和DNMT3L蛋白水平过表达，而DNMT2表达降低。此外，与原发肿瘤相比，复发肿瘤中DNMT1和DNMT3L表达增加。DNMT3A、DNMT1和DNMT3B的mRNA水平与总生存期相关。结论：本研究表明，DNMT1和DNMT3L在原发高级别EOC中上调，并在复发中进一步增加；而DNMT3A仅在癌症进展的早期阶段上调。DNMT2的下调则突显了该基因在卵巢癌中推测的肿瘤抑制活性。
肿瘤(癌症)患者之家