Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
Tissue Bank Unit, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
Pathol Res Pract. 2018 Jan;214(1):134-143. doi: 10.1016/j.prp.2017.10.005. Epub 2017 Oct 9.
Dysregulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) is associated with the pathogenesis of various types of cancer. It has been previously shown that DNMT1 is frequently expressed in diffuse large B-cell lymphoma (DLBCL), however its functions remain to be elucidated in the disease. In this study, we gene expression profiled (GEP) shRNA targeting DNMT1(shDNMT1)-treated germinal center B-cell-like DLBCL (GCB-DLBCL)-derived cell line (i.e. HT) compared with non-silencing shRNA (control shRNA)-treated HT cells. Independent gene set enrichment analysis (GSEA) performed using GEPs of shRNA-treated HT cells and primary GCB-DLBCL cases derived from two publicly-available datasets (i.e. GSE10846 and GSE31312) produced three separate lists of enriched gene sets for each gene sets collection from Molecular Signatures Database (MSigDB). Subsequent Venn analysis identified 268, 145 and six consensus gene sets from analyzing gene sets in C2 collection (curated gene sets), C5 sub-collection [gene sets from gene ontology (GO) biological process ontology] and Hallmark collection, respectively to be enriched in positive correlation with DNMT1 expression profiles in shRNA-treated HT cells, GSE10846 and GSE31312 datasets [false discovery rate (FDR) <0.05]. Cell cycle progression and DNA replication were among the significantly enriched biological processes (FDR <0.05). Expression of genes involved in the activation of cell cycle and DNA replication (e.g. CDK1, CCNA2, E2F2, PCNA, RFC5 and POLD3) were highly correlated (r>0.8) with DNMT1 expression and significantly downregulated (log fold-change <-1.35; p<0.05) following DNMT1 silencing in HT cells. These results suggest the involvement of DNMT1 in the activation of cell cycle and DNA replication in DLBCL cells.
DNA（胞嘧啶-5）-甲基转移酶 1（DNMT1）的失调与各种类型癌症的发病机制有关。先前已经表明，DNMT1在弥漫性大 B 细胞淋巴瘤（DLBCL）中经常表达，但其在疾病中的功能仍有待阐明。在这项研究中，我们对靶向 DNMT1 的 shRNA 处理的生发中心 B 细胞样 DLBCL（GCB-DLBCL）衍生细胞系（即 HT）进行了基因表达谱（GEP）分析，与非沉默 shRNA（对照 shRNA）处理的 HT 细胞进行了比较。使用来自两个公开可用数据集（即 GSE10846 和 GSE31312）的 shRNA 处理的 HT 细胞和原发性 GCB-DLBCL 病例的 GEP 进行独立的基因集富集分析（GSEA），为每个基因集从分子特征数据库（MSigDB）产生了三个单独的富集基因集列表。随后的 Venn 分析从 C2 集合（已编辑基因集）、C5 子集合[基因集来自基因本体论（GO）生物学过程本体论]和 Hallmark 集合分析基因集中分别鉴定了 268、145 和 6 个共识基因集，以与 shRNA 处理的 HT 细胞、GSE10846 和 GSE31312 数据集中的 DNMT1 表达谱呈正相关（假发现率（FDR）<0.05）。细胞周期进展和 DNA 复制是显著富集的生物学过程之一（FDR<0.05）。参与细胞周期和 DNA 复制激活的基因的表达（例如 CDK1、CCNA2、E2F2、PCNA、RFC5 和 POLD3）与 DNMT1 表达高度相关（r>0.8），并且在 HT 细胞中 DNMT1 沉默后显著下调（对数倍数变化<-1.35；p<0.05）。这些结果表明 DNMT1 参与了 DLBCL 细胞中细胞周期和 DNA 复制的激活。
