表观遗传改变的 microRNAs 和 DNA 甲基化导致结直肠癌肝转移。
Epigenetic Alternations of MicroRNAs and DNA Methylation Contribute to Liver Metastasis of Colorectal Cancer.
机构信息
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China.
出版信息
Dig Dis Sci. 2019 Jun;64(6):1523-1534. doi: 10.1007/s10620-018-5424-6. Epub 2019 Jan 2.
BACKGROUND
Liver metastasis is a major cause of mortality in colorectal cancer (CRC). Epigenetic alternations could serve as biomarkers for cancer diagnosis and prognosis. In this study, we analyzed microarray data in order to identify core genes and pathways which contribute to liver metastasis in CRC under epigenetic regulations.
MATERIALS AND METHODS
Data of miRNAs (GSE35834, GSE81582), DNA methylation (GSE90709, GSE77955), and mRNA microarrays (GSE68468, GSE81558) were downloaded from GEO database. Differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially methylated genes (DMGs) were obtained by GEO2R. The target genes of DEMs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. Protein-protein interaction (PPI) network was constructed in STRING and visualized using Cytoscape.
RESULTS
In liver metastasis, miR-143-3p, miR-10b-5p, miR-21-5p, and miR-518f-5p were down-regulated, while miR-122-5p, miR-885-5p, miR-210-3p, miR-130b-5p, miR-1275, miR-139-5p, miR-139-3p, and miR-1290 were up-regulated compared with primary CRC. DEGs targeted by altered miRNAs were enriched in pathways including complement, PPAR signaling, ECM-receptor interaction, spliceosome, and focal adhesion. In addition, aberrant DNA methylation-regulated genes showed enrichment in pathways of amino acid metabolism, calcium signaling, TGF-beta signaling, cell cycle, spliceosome, and Wnt signaling.
CONCLUSION
Our study identified a series of differentially expressed genes which are associated with epigenetic alternations of miRNAs and DNA methylation in colorectal liver metastasis. Up-regulated genes of SLC10A1, MAPT, SHANK2, PTH1R, and C2, as well as down-regulated genes of CAB39, CFLAR, CTSC, THBS1, and TRAPPC3 were associated with both miRNA and DNA methylation, which might become promising biomarker of colorectal liver metastasis in future.
背景
肝转移是结直肠癌（CRC）患者死亡的主要原因。表观遗传改变可以作为癌症诊断和预后的生物标志物。在这项研究中，我们分析了微阵列数据，以鉴定在 CRC 肝转移中受表观遗传调控的核心基因和途径。
材料与方法
从 GEO 数据库下载 miRNA（GSE35834、GSE81582）、DNA 甲基化（GSE90709、GSE77955）和 mRNA 微阵列（GSE68468、GSE81558）数据。通过 GEO2R 获得差异表达基因（DEGs）、差异表达 microRNAs（DEMs）和差异甲基化基因（DMGs）。通过 miRWalk 预测 DEMs 的靶基因。使用 DAVID 数据库进行功能和富集分析。在 STRING 中构建蛋白质-蛋白质相互作用（PPI）网络，并使用 Cytoscape 可视化。
结果
在肝转移中，miR-143-3p、miR-10b-5p、miR-21-5p 和 miR-518f-5p 下调，而 miR-122-5p、miR-885-5p、miR-210-3p、miR-130b-5p、miR-1275、miR-139-5p、miR-139-3p 和 miR-1290 上调。受改变的 miRNA 靶向的 DEGs 富集在补体、PPAR 信号、ECM-受体相互作用、剪接体和焦点黏附途径中。此外，异常 DNA 甲基化调控基因在氨基酸代谢、钙信号、TGF-β信号、细胞周期、剪接体和 Wnt 信号途径中富集。
结论
本研究鉴定了一系列与结直肠癌肝转移中 miRNA 和 DNA 甲基化的表观遗传改变相关的差异表达基因。SLC10A1、MAPT、SHANK2、PTH1R 和 C2 的上调基因，以及 CAB39、CFLAR、CTSC、THBS1 和 TRAPPC3 的下调基因与 miRNA 和 DNA 甲基化均相关，这些基因可能成为未来结直肠癌肝转移有前途的生物标志物。
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