miR-497和miR-34a在铂敏感和铂耐药卵巢上皮癌患者中的表达差异及机制研究
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篇名: miR-497和miR-34a在铂敏感和铂耐药卵巢上皮癌患者中的表达差异及机制研究
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摘要: 目的:探讨微小核糖核酸miR-497和miR-34a在铂敏感和铂耐药卵巢上皮癌(EOC)患者中表达的差异及机制。方法:选取2008年1月-2012年1月于我院妇产科行卵巢癌分期手术或肿瘤细胞减灭术的EOC患者72例,术后均行以铂类药物为基础的规范化疗,并进行随访(时间为2008年7月-2016年7月)。根据患者对铂类药物的敏感性将其分为铂敏感组(42例)和铂耐药组(30例)。采用实时荧光定量聚合酶链反应法检测两组患者肿瘤组织中miR-497和miR-34a的表达水平,并考察其与患者总生存时间的相关性;采用巢式降落式甲基化特异性聚合酶链反应法检测患者miR-497和miR-34a启动子区DNA甲基化水平,采用蛋白印迹法考察组蛋白H3第9位赖氨酸残基二甲基化(H3K9me2)水平,采用染色质免疫共沉淀法检测miR-497和miR-34a启动子区H3K9me2水平。结果:铂敏感组患者miR-497和miR-34a的表达水平均显著高于铂耐药组,差异均有统计学意义(P<0.05);72例患者的总生存期为(45.7±17.5)个月,与其miR-497和miR-34a表达水平呈正相关(r2分别为0.271 4、0.378 2,P<0.01)。铂耐药组患者miR-497和miR34a启动子区DNA甲基化水平均显著高于铂敏感组,且其启动子区H3K9me2水平也显著高于铂敏感组,差异均有统计学意义(P<0.05或P<0.01);而铂耐药组患者H3K9me2水平虽略高于铂敏感组,但差异无统计学意义(P>0.05)。结论:EOC患者肿瘤组织中miR-497和miR-34a的表达水平与铂化疗的敏感性及患者的生存时间有关,启动子区DNA甲基化和组蛋白甲基化可能是其表达变化的机制之一。
ABSTRACT: OBJECTIVE: To investigate the expression difference and its mechanism of miR-497 and miR-34a in platinum-sensitive and platinum-resistant epithelial ovarian carcinoma (EOC) patients. METHODS: A total of 72 EOC patients underwent ovarian cancer staging surgery or cytoreductive surgery were selected from department of gynaecology and obstetriscs of our hospital during Jan. 2008-Jan. 2012. They received standardized platinum chemotherapy after surgery and were followed up (during Jul. 2008-Jul.2016). According to the sensitivity to platinum, those patients were divided into platinum-sensitive group (42 cases) and platinum-resistant group (30 cases) . Real-time fluorescent quantitative PCR was adopted to detect the expression of miR-497 and miR-34a in tumor tissue, and the relationship of it with total survival period was investigated. The levels of DNA methylation of miR-497 and miR-34a promoter region were determined by nest type land type methylation specific PCR. Western blot assay was used to detect the H3K9 dimethylation (H3K9me2) levels. The H3K9me2 levels of miR-497 and miR-34a promoter region were determined by chromatin immunoprecipitation method. RESULTS: The expression levels of miR-497 and miR-34a in platinum-sensitive group were significantly higher than platinum-resistant group, with statistical significance (P<0.05). Total survival period of 72 patients was (45.7±17.5) months, which was positively correlated with the expression levels of miR-497 and miR-34a (r2 were 0.271 4, 0.378 2, P<0.01). The DNA methylation of miR-497 and miR-34a promoter region in platinum-resistant group was significantly higher than platinum-sensitive group, and H3K9me2 level of promoter region was significantly higher than platinum-sensitive group, with statistical significance (P<0.05 or P<0.01). H3K9me2 levels of platinum-resistant group were slightly higher than that of platinum-sensitive group, but there was no statistical significance (P>0.05). CONCLUSIONS: The expression of miR-497 and miR-34a in tumor tissue of EOC patients are related to the sensitivity of platinum chemotherapy and the survival time of patients. DNA methylation and histone methylation of promoter region may be one of the mechanisms of their expression changes.
期刊: 2017年第28卷第17期
作者: 曹丽娟,刘文博
AUTHORS: CAO Lijuan,LIU Wenbo
关键字: 微小核糖核酸;miR-497;miR-34a;卵巢上皮癌;铂耐药;DNA甲基化;组蛋白甲基化;启动子区
KEYWORDS: MicroRNAs; miR-497; miR-34a; Epithelial ovarian cancer; Platinum resistant; DNA methylation; Histone methylation; Promoter region
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