Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma.
Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma.
复制标题
整体癌症特异性microRNA簇低甲基化与非B型非C型肝细胞癌的发展在功能上相关。
DOI：
10.1186/s12943-016-0514-6
复制
发表时间：
2016-04-30
期刊：
影响因子：
37.3
通讯作者：
Tanaka Y
中科院分区：
文献类型：
--
作者：
Nojima M;Matsui T;Tamori A;Kubo S;Shirabe K;Kimura K;Shimada M;Utsunomiya T;Kondo Y;Iio E;Naito Y;Ochiya T;Tanaka Y
虽然乙型和丙型肝炎病毒感染已得到抑制，但在一些发达国家，非乙型非丙型肝细胞癌（NBNC-HCC）的发病率被认为正在上升，这些国家的肝癌患者中病毒感染的患病率非常高（例如日本、韩国和意大利）。为了阐明 NBNC-HCC 中的关键分子变化，我们通过统计模型整合了三个大型数据集，这些数据集涉及全基因组 DNA 甲基化（N = 43 对）和 mRNA/miRNA 表达（分别为 N = 15 和 24 对）的全面阵列分析。 miRNA 编码区 DNA 甲基化的层次聚类清楚地将 NBNC-HCC 组织样本与相关背景组织区分开来，揭示了显着的肿瘤特异性低甲基化簇。此外，肿瘤样本中的 miRNA 簇高度低甲基化（非簇状 miRNA 的中位甲基化变化：-2.3%，簇状 miRNA：-24.6%）。超过 90% 的样本中 CpG 低甲基化的比例为 miRNA 簇内所有 CpG 的 55.9%，峰值甲基化水平从 84% 急剧转变为 39%。经过统计调整，miRNA编码区甲基化水平的差异与其表达变化呈正相关。接受者操作特征（ROC）分析揭示了簇-miRNA甲基化的巨大区分能力。此外，在保守且高度匹配的miRNA位点中，miRNA甲基化变化与相应靶基因表达呈负相关。我们观察到 miRNA 簇区域甲基化水平急剧负移。 miRNA甲基化状态的变化比各自miRNA表达的变化更能指示靶基因表达和病理诊断，这表明全基因组miRNA甲基化对肿瘤发生的重要性。我们的研究动态总结了 NBNC-HCC 中的全局 miRNA 低甲基化及其全基因组范围的后果。本文的在线版本 (doi:10.1186/s12943-016-0514-6) 包含补充材料，可供授权用户使用。
While hepatitis B and C viral infection have been suppressed, non-B non-C hepatocellular carcinoma (NBNC-HCC) is considered to be rising in incidence terms in some developed countries where prevalence of those viral infections among HCC patients had been very high (such as Japan, Korea, and Italy). To elucidate critical molecular changes in NBNC-HCC, we integrated three large datasets relating to comprehensive array-based analysis of genome-wide DNA methylation (N = 43 pairs) and mRNA/miRNA expression (N = 15, and 24 pairs, respectively) via statistical modeling. Hierarchical clustering of DNA methylation in miRNA coding regions clearly distinguished NBNC-HCC tissue samples from relevant background tissues, revealing a remarkable tumor-specific hypomethylation cluster. In addition, miRNA clusters were extremely hypomethylated in tumor samples (median methylation change for non-clustered miRNAs: -2.3%, clustered miRNAs: -24.6%). The proportion of CpGs hypomethylated in more than 90% of the samples was 55.9% of all CpGs within miRNA clusters, and the peak methylation level was drastically shifted from 84% to 39%. Following statistical adjustment, the difference in methylation levels within miRNA coding regions was positively associated with their expression change. Receiver operating characteristic (ROC) analysis revealed a great discriminatory ability in respect to cluster-miRNA methylation. Moreover, miRNA methylation change was negatively correlated with corresponding target gene expression amongst conserved and highly matched miRNA sites. We observed a drastic negative shift of methylation levels in miRNA cluster regions. Changes in methylation status of miRNAs were more indicative of target gene expression and pathological diagnosis than respective miRNA expression changes, suggesting the importance of genome-wide miRNA methylation for tumor development. Our study dynamically summarized global miRNA hypomethylation and its genome-wide scale consequence in NBNC-HCC. The online version of this article (doi:10.1186/s12943-016-0514-6) contains supplementary material, which is available to authorized users.