Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Mol Med Rep. 2018 Nov;18(5):4446-4456. doi: 10.3892/mmr.2018.9441. Epub 2018 Sep 3.
Aberrant DNA methylation is the most common type of epigenetic alteration and is associated with many types of cancer. Although previous studies have provided a few novel DNA methylation markers in hepatocellular carcinoma (HCC), specific DNA methylation patterns and comparisons of the aberrant alterations in methylation between HCC and normal liver cell lines have not yet been reported. Therefore, in the present study the Illumina Infinium HumanMethylation 450K BeadChip was employed to identify the genome‑wide aberrant DNA methylation profiles of Huh7 and L02 cells. Following Bonferroni adjustment, 102,254 differentially methylated CpG sites (covering 26,511 genes) were detected between Huh7 and L02 cells. Of those CpG sites, 62,702 (61.3%) sites were hypermethylated (covering 12,665 genes) and 39,552 (38.7%) sites were hypomethylated (covering 13,846 genes). The results of the present study indicated that 40.3% of the CpG sites were in CpG island regions, 20.7% were in CpG shores and 8.8% were in shelf regions. A total of 57.3% hypermethylated CpG sites and 39.4% of the hypomethylated CpG sites had a |β‑Difference| ≥50%. Within the significant differentially methylated CpG sites, 490 genes were located within 598 differentially methylated regions. Gene Ontology enrichment analysis revealed that 2,107 differentially methylated genes were associated with 'biological process', 13,351 differentially methylated genes were associated with 'molecular function', and 18,041 differentially methylated genes were associated with 'cellular component'. Kyoto Encyclopedia of Genes and Genomes pathway‑based analysis revealed 43 signaling pathways that were associated with 5,195 differentially methylated genes. These results demonstrated that aberrant DNA methylation may be a key and common event underlying the tumorigenesis of Huh7 cells. The present study also identified many subsets of hypo‑ or hyper‑methylated CpG sites, genes and signaling pathways, which have an importance in the occurrence and development of HCC.
异常的 DNA 甲基化是最常见的表观遗传改变类型，与许多类型的癌症有关。尽管先前的研究已经在肝细胞癌 (HCC) 中提供了一些新的 DNA 甲基化标记物，但尚未报道 HCC 和正常肝细胞系之间甲基化异常改变的特定 DNA 甲基化模式和比较。因此，本研究采用 Illumina Infinium HumanMethylation 450K BeadChip 鉴定了 Huh7 和 L02 细胞的全基因组异常 DNA 甲基化谱。经过 Bonferroni 调整，在 Huh7 和 L02 细胞之间检测到 102,254 个差异甲基化 CpG 位点（覆盖 26,511 个基因）。在这些 CpG 位点中，62,702 个（61.3%）位点呈高甲基化（覆盖 12,665 个基因），39,552 个（38.7%）位点呈低甲基化（覆盖 13,846 个基因）。本研究结果表明，40.3%的 CpG 位点位于 CpG 岛区域，20.7%位于 CpG 海岸，8.8%位于 shelf 区域。总共 57.3%的高甲基化 CpG 位点和 39.4%的低甲基化 CpG 位点的 |β-Difference|≥50%。在显著差异甲基化 CpG 位点内，490 个基因位于 598 个差异甲基化区域内。基因本体论富集分析显示，2107 个差异甲基化基因与“生物过程”有关，13351 个差异甲基化基因与“分子功能”有关，18041 个差异甲基化基因与“细胞成分”有关。京都基因与基因组百科全书通路分析显示，有 43 个信号通路与 5195 个差异甲基化基因相关。这些结果表明，异常的 DNA 甲基化可能是 Huh7 细胞肿瘤发生的关键和常见事件。本研究还鉴定了许多低甲基化或高甲基化 CpG 位点、基因和信号通路亚群，这些亚群在 HCC 的发生和发展中具有重要意义。
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