[某些微小RNA基因的甲基化参与肺癌中其靶基因视黄酸受体β2（RAR-beta2）和核因子κB抑制蛋白α（NKIRAS1）表达的调控]
[Methylation of some miRNA genes is involved in the regulation of their target genes RAR-beta2 and NKIRAS1 expression in lung cancer].
作者信息
Khodyrev D S, Pronina I V, Rykov S V, Beresneva E V, Fridman M V, Kazubskaia T P, Loginov V I, Braga É A
出版信息
Mol Biol (Mosk). 2012 Sep-Oct;46(5):773-85.
To date, there are more than two thousand human miRNAs, each of them may be involved in the regulation of hundreds of protein coding target genes. Methylation of CpG-islands, in turn, affects miRNAs gene expression. Our aim was to evaluate the role of methylation in the regulation of miRNA gene expression and, consequently, in the regulation of expression of target genes in primary lung tumors. Using a common collection of non-small cell lung cancer samples we performed a comprehensive study, including analysis of the methylation status and expression levels of some miRNA genes and their potential target genes on chromosome 3: RAR-beta2 and NKIRAS1. Increased frequency of methylation in lung tumors compared to histologically normal tissue was revealed for miR-9-1 and miR-34b/c genes with significant statistics (P < or = 0.05 by Fisher exact test) and for miR-9-3 and miR-193a was marginally significant (P < or = 0.1). Significant correlation was revealed between alterations of methylation and expression level of miR-9-1 gene (P = 5 x 10(-12) by Spearman) in the lung tumors, this suggests the role of methylation in the regulation of expression of this miRNA genes. Besides, a statistically significant negative correlation (P = 3 x 10(-12)-5 x 10(-13) by Spearman) was found between alterations of expression levels of miR-9-1 and miR-17and RAR-beta2 target gene and also between expression level alterations of miR-17 and NKIRAS1 that was not previously analyzed. The inverse relationship between expression levels of miRNA genes and their target genes is consistent with the known mechanism of suppression of protein coding genes expression under the action of miRNAs. For the first time significant correlations (P = 3 x 10(-10)-4 x 10(-13) by Spearman) were shown between alterations of methylation status of miRNA genes (miR-9-1, miR-9-3, miR-34b/c, miR-193a) and the expression level of RAR-beta2 target gene and between alterations of methylation status of miR-34b/c, and miR-193a and the expression level of NKIRAS1 target gene in the primary lung tumors, which suggests the possibility of indirect effects of methylation of miRNA genes on expression level of target genes.
迄今为止，人类miRNA有两千多种，每种miRNA可能参与数百种蛋白质编码靶基因的调控。反过来，CpG岛的甲基化会影响miRNA基因的表达。我们的目的是评估甲基化在miRNA基因表达调控中的作用，进而评估其在原发性肺肿瘤靶基因表达调控中的作用。我们使用非小细胞肺癌样本的通用集合进行了一项全面研究，包括分析一些miRNA基因及其位于3号染色体上的潜在靶基因RAR-beta2和NKIRAS1的甲基化状态和表达水平。与组织学正常组织相比，miR-9-1和miR-34b/c基因在肺肿瘤中的甲基化频率增加，差异具有统计学意义（Fisher精确检验，P≤0.05），miR-9-3和miR-193a的甲基化频率增加具有边缘统计学意义（P≤0.1）。在肺肿瘤中，miR-9-1基因的甲基化改变与表达水平之间存在显著相关性（Spearman检验，P = 5×10⁻¹²），这表明甲基化在该miRNA基因表达调控中起作用。此外，发现miR-9-1和miR-17的表达水平改变与RAR-beta2靶基因之间以及miR-17与NKIRAS1的表达水平改变之间存在统计学显著的负相关性（Spearman检验，P = 3×10⁻¹² - 5×10⁻¹³），而NKIRAS1此前未被分析过。miRNA基因与其靶基因表达水平之间的反向关系与miRNA作用下蛋白质编码基因表达抑制的已知机制一致。首次发现原发性肺肿瘤中miRNA基因（miR-9-1、miR-9-3、miR-34b/c、miR-193a）的甲基化状态改变与RAR-beta2靶基因的表达水平之间以及miR-34b/c和miR-193a的甲基化状态改变与NKIRAS1靶基因的表达水平之间存在显著相关性（Spearman检验，P = 3×10⁻¹⁰ - 4×10⁻¹³），这表明miRNA基因甲基化可能对靶基因表达水平产生间接影响。
Zotero 插件