Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY USA.
Epigenetics. 2012 Nov;7(11):1230-7. doi: 10.4161/epi.22140. Epub 2012 Sep 13.
Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
成熟的 microRNAs（miRNAs）是一类参与翻译后基因沉默的小型非编码 RNA。先前的研究发现，miRNAs 的下调是包括肝细胞癌（HCC）在内的实体瘤的一个常见特征。我们采用全基因组方法检验了这样一个假设，即 miRNA 宿主基因中的 DNA 甲基化改变可能导致 HCC 中 miRNA 表达的失调。我们分析了来自 62 例台湾 HCC 病例的肿瘤和相邻非肿瘤组织，使用包括 64 个宿主基因中 110 个 miRNA 的 254 个 CpG 位点的 Infinium HumanMethylation27 DNA Analysis BeadChips。在一个包含 37 例 HCC 肿瘤和非肿瘤组织的亚集中，测量了三个鉴定的 miRNA（miR-10a、miR-10b 和 miR-196b）的表达水平。在肿瘤和相邻非肿瘤组织中，共有 27 个宿主基因的 54 个 CpG 位点的 DNA 甲基化水平存在显著差异，其中 53 个在肿瘤组织中呈显著高甲基化。在 54 个显著 CpG 位点中，有 15 个位点的肿瘤/非肿瘤变化超过 2 倍，17 个位点的差异超过 10%，10 个位点同时具有这两个特征[包括 miR-10a、miR-10b 和 miR-196b 的宿主基因中的 8 个显著高甲基化 CpG 位点（分别为 HOXB4、HOXD4 和 HOXA9）]。与非肿瘤组织相比，miR-10a 在肿瘤组织中的表达明显下调（0.50 比 1.73，p = 0.031）。HOXB4 甲基化改变和 miR-10a 失调的一致性为 73.5%。miR-10b 的表达没有明显变化。出乎意料的是，miR-196b 在肿瘤组织中明显上调，与非肿瘤组织相比（p = 0.0001）。这些数据表明，异常的 DNA 甲基化可能导致 HCC 肿瘤组织中 miR-10a 的失调。
