Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2021 Feb 2;22(3):1474. doi: 10.3390/ijms22031474.
N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein-protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (), exodeoxyribonuclease 1 (), ser-ine/threonine-protein kinase Nek2 (), baculoviral IAP repeat-containing protein 5 (), hyaluronan mediated motility receptor (), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (), ca-sein kinase I isoform epsilon (), cytoskeleton-associated protein 5 (), and inner centromere protein (), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein-protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (), filensin (), tubulin-specific chaperone D (), histone-lysine N-methyltransferase PRDM16 (), phosphorylase b ki-nase regulatory subunit alpha (), serine/threonine-protein kinase BRSK2 (), Arf-GAP with coiled-coil (), general transcription factor 3C polypep-tide 2 (), and guanine nucleotide exchange factor MSS4 (). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.
N6-甲基腺苷(m6A)修饰在 RNA 中发挥着重要作用,它可以在多个水平上改变基因表达,甚至改变功能,如 RNA 剪接、稳定性、易位和翻译。在这项研究中,我们旨在对肝癌中的 m6A RNA 甲基化相关基因进行全面分析,包括 m6A RNA 甲基化调节剂和 m6A RNA 甲基化修饰基因,并研究其与生存和临床特征的关系。本研究的数据来自癌症基因组图谱(TCGA)中广泛报道的 m6A RNA 甲基化相关基因在肝癌中的表达情况,通过单因素方差分析、单变量 Cox 回归、蛋白质-蛋白质相互作用网络、基因富集分析、特征筛选、风险预后模型、相关性分析和共识聚类分析进行分析。结果共发现了 405 个 m6A RNA 甲基化相关基因。其中,DNA 拓扑异构酶 2-α()、核酸外切酶 1()、丝氨酸/苏氨酸蛋白激酶 Nek2()、杆状病毒 IAP 重复蛋白 5()、透明质酸介导的运动受体()、染色体结构维持蛋白 4(SMC4)、布卢姆综合征蛋白()、酪蛋白激酶 I 同工型 epsilon()、细胞骨架相关蛋白 5()和着丝粒蛋白(),这些都是 m6A RNA 甲基化修饰基因,被认为是基于蛋白质-蛋白质相互作用分析的枢纽基因。风险预后模型显示,性别、AJCC 分期、分级、T 和 N 在高风险组和低风险组之间存在显著差异。随机森林构建的预测模型的 AUC(评价参数)为 0.7。此外,通过共识聚类分析将两组分为两个亚组,其中分期、分级和 T 不同。我们确定了两个聚类中表达差异显著的重要基因,包括尿嘧啶-胞嘧啶激酶 2()、细丝蛋白()、微管特异性伴侣 D()、组蛋白赖氨酸 N-甲基转移酶 PRDM16()、磷酸化酶 b 激酶调节亚基 α()、丝氨酸/苏氨酸蛋白激酶 BRSK2()、卷曲螺旋 ARF-GAP()、通用转录因子 3C 多肽 2()和鸟嘌呤核苷酸交换因子 MSS4()。在本研究中,系统分析了肝癌中的 m6A RNA 甲基化相关基因,包括表达、相互作用、功能和预后价值,为肝癌中 m6A RNA 甲基化提供了重要的理论基础。这 9 个重要的 m6A 相关基因可能是患者生存时间的预后标志物。