Expression profiles and prognostic significance of RNA N6-methyladenosine-related genes in patients with hepatocellular carcinoma: evidence from independent datasets
Expression profiles and prognostic significance of RNA N6-methyladenosine-related genes in patients with hepatocellular carcinoma: evidence from independent datasets
复制标题
肝细胞癌患者中 RNA N6-甲基腺苷相关基因的表达谱和预后意义：来自独立数据集的证据
DOI：
10.2147/cmar.s191565
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Jian, Zhixiang
中科院分区：
文献类型：
--
作者：
Zhou, Yu;Yin, Zi;Jian, Zhixiang
背景：N6-甲基腺苷（m6 A）是哺乳动物RNA最常见的修饰。新出现的证据表明，m6 A在多种生物学活动中具有关键作用，但对其在癌症发病机制中的作用知之甚少。在此，我们通过分析四个独立的数据集，报告了12个m6 A相关基因在肝细胞癌（HCC）中的表达谱和预后相关性。材料与方法：在162例接受根治性切除术的HCC患者样本中检测了12个m6 A相关基因的RNA水平（广东省人民医院数据集）。我们还分析了癌症基因组图谱肝HCC数据集和两个基因表达综合数据集（GSE 14520，GSE 63898）中m6 A相关基因的表达谱。采用Kaplan-Meier生存曲线进行log-rank检验和多因素考克斯回归分析。进行基因集富集分析（GSEA）以鉴定相关的KEGG途径。结果：5个基因（胃L3、YTHDF 1、YTHDF 2、YTHDF 3和EIF 3）在所有4个数据集中显示一致的上调。胃癌组织中只有一个基因的异常表达与OS有关，而其他10个基因的异常表达与OS无关。多变量考克斯回归分析证实了胃L3和YTHDF 1对OS的独立预测价值。我们进一步根据胃L3和YTHDF 1的中位表达值将患者分为三组。在所有数据集中，低胃L3/低YTHDF 1组显示出比其他组更好的预后。GSEA结果显示，胃L3和YTHDF 1均调控肝癌细胞周期、RNA剪接、DNA复制、碱基切除修复和RNA降解。结论：胃L3和YTHDF 1在肝癌组织中均表达上调，是独立的预后不良因素。结论：胃癌L3和YTHDF 1联合表达可作为反映肝癌恶性程度和评估预后的生物学指标。
Background: N6-methyladenosine (m6A) is the most prevalent modification of mammalian RNA. Emerging evidence suggest that m6A has critical roles in multiple biological activities, but little is known about its roles in cancer pathogenesis. Herein, we report the expression profiles and prognostic relevance of twelve m6A-related genes in hepatocellular carcinoma (HCC) by analyzing four independent datasets. Materials and methods: RNA levels of twelve m6A-related genes were detected in samples of 162 HCC patients who underwent curative resection (the Guangdong General Hospital dataset). We additionally analyzed the expression profiles of m6A-related genes in The Cancer Genome Atlas liver HCC dataset and two Gene Expression Omnibus datasets (GSE14520, GSE63898). Prognostic value of genes was evaluated by Kaplan–Meier curves of overall survival (OS) with the log-rank test and multivariate Cox regression analysis. Gene set enrichment analysis (GSEA) was conducted to identify associated KEGG pathways. Results: Five genes (METTL3, YTHDF1, YTHDF2, YTHDF3, and EIF3) showed consistent upregulation in all four datasets. Abnormal expressions of either METTL3 or YTHDF1 but not the other ten genes were associated with OS. Protein expression of METTL3 and YTHDF1 were confirmed in HCC tissues by immunohistochemical staining. Multivariate Cox regression analysis confirmed the independent predictive value of both METTL3 and YTHDF1 on OS. We further divided patients into three groups based on the median expression values of METTL3 and YTHDF1. In all datasets, the low METTL3/low YTHDF1 group showed a consistent better prognosis than other groups. GSEA revealed that both METTL3 and YTHDF1 regulate HCC cell cycle, RNA splicing, DNA replication, base excision repair, and RNA degradation. Conclusion: Both METTL3 and YTHDF1 were upregulated in HCC, and they were independent poor prognostic factors. Combination of METTL3 and YTHDF1 can be regarded as the biological marker that reflect malignant degree and evaluate prognosis in HCC.