Tan Weiqi, Gu Jian, Huang Maosheng, Wu Xifeng, Hildebrandt Michelle A T
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
Mol Carcinog. 2015 Jun;54 Suppl 1(Suppl 1):E45-51. doi: 10.1002/mc.22149. Epub 2014 Mar 24.
Aberrant microRNA (miRNA) expression is involved in tumorigenesis of several cancers, including non-small cell lung cancer (NSCLC). Furthermore, expression of some miRNAs has been shown to be under epigenetic regulation. However, less is known regarding the role of miRNA methylation in NSCLC development or clinical outcomes. Therefore, we tested miRNA methylation patterns by quantitative real-time methylation-specific PCR for a panel of candidate miRNAs in 19 NSCLC paired tumor and adjacent normal tissues. For assessment of survival, methylation was measured in a total of 97 tumor tissues with complete clinical and follow-up data. Analysis was also performed for correlation with age at diagnosis, gender, smoking, and stage. Significant differences in methylation patterns were observed for 9 of the 12 miRNAs, all due to hypermethylation in the tumor tissue. Individuals with the highest levels of methylated miR-127 were at a significantly increased risk of dying with a hazard ratio of 1.93 (95% CI 1.17-3.19; P = 0.010), in univariate analysis and remained significant after adjusting for age, gender, and stage (HR 1.97; 95% CI 1.15-3.40; P = 0.014). This increase in risk due to increased methylation were accompanied by significant, dramatic difference in survival duration of 17 months (P = 0.0089). Six of the 12 miRNAs were significantly positively correlated with age at diagnosis. Additionally, methylation of miR-127 was significantly greater in higher stage tumors compared to lower stage tumors (P = 0.0039). However, no significant associations between smoking and gender with miRNA methylation were observed. Our results demonstrate that miRNA methylation plays a role in NSCLC tumorigenesis and prognosis.
异常的微小RNA（miRNA）表达与包括非小细胞肺癌（NSCLC）在内的多种癌症的肿瘤发生有关。此外，一些miRNA的表达已被证明受表观遗传调控。然而，关于miRNA甲基化在NSCLC发展或临床结局中的作用，人们了解较少。因此，我们通过定量实时甲基化特异性PCR检测了19对NSCLC肿瘤组织和相邻正常组织中一组候选miRNA的甲基化模式。为了评估生存率，在总共97个具有完整临床和随访数据的肿瘤组织中测量了甲基化水平，并对其与诊断时的年龄、性别、吸烟情况和分期的相关性进行了分析。在12个miRNA中的9个中观察到甲基化模式存在显著差异，均是由于肿瘤组织中的高甲基化。甲基化miR-127水平最高的个体死亡风险显著增加，单因素分析中风险比为1.93（95%可信区间1.17 - 3.19；P = 0.010），在调整年龄、性别和分期后仍具有显著性（风险比1.97；95%可信区间1.15 - 3.40；P = 0.014）。由于甲基化增加导致的风险增加伴随着生存时间显著延长17个月（P = 0.0089）。12个miRNA中的6个与诊断时的年龄显著正相关。此外，与低分期肿瘤相比，高分期肿瘤中miR-127的甲基化显著更高（P = 0.0039）。然而，未观察到吸烟和性别与miRNA甲基化之间存在显著关联。我们的结果表明，miRNA甲基化在NSCLC的肿瘤发生和预后中起作用。
