m^(6)A RNA甲基化调节因子与肝细胞癌预后的关系

Relationship between m^(6)A RNA methylation regulator and prognosis of hepatocellular carcinoma

目的探讨N^(6)-甲基腺嘌呤(m^(6)A)RNA甲基化调节因子与肝细胞癌(HCC)预后的关系。方法从美国国家癌症研究所基因组数据共享中心下载HCC样本和正常对照样本的RNA-seq转录组数据,并收集HCC样本临床病理资料。从RNA-seq转录组数据中获取FTO、YTHDC2、YTHDC1、ALKBH5、KIAA1429、METTL3、HNRNPC、YTHDF2、RBM15、YTHDF1、WTAP、METTL14、ZC3H13等十三种m^(6)A RNA甲基化调节因子的表达数据,比较HCC样本和正常对照样本m^(6)A RNA甲基化调节因子表达。采用单因素Cox回归分析和Lasso Cox回归分析筛选与HCC预后相关的m^(6)A RNA甲基化调节因子,并构建风险模型,分析风险模型与HCC预后的关系。结果 HCC样本FTO、YTHDC2、YTHDC1、ALKBH5、KIAA1429、METTL3、HNRNPC、YTHDF2、RBM15、YTHDF1、WTAP表达均高于正常对照样本(P均<0.01),而两样本METTL14、ZC3H13表达比较差异均无统计学意义(P均>0.05)。YTHDF1、ZC3H13、YTHDF2、METTL3和KIAA1429等五种m^(6)A RNA甲基化调节因子是影响HCC预后的危险因素(P均<0.05)。其中,ZC3H13高表达者预后良好,而YTHDF1、YTHDF2、METTL3、KIAA1429高表达者预后较差。根据YTHDF1、ZC3H13、YTHDF2、METTL3、KIAA1429等五种m^(6)A RNA甲基化调节因子构建HCC预后风险模型,然后将HCC患者分为高风险者与低风险者,高风险者5年生存率明显低于低风险者(P<0.05);ROC曲线分析显示,该风险模型的曲线下面积为0.619。单因素和多因素Cox回归分析显示,风险模型评分是影响HCC预后的独立危险因素(P<0.01)。结论 m^(6)A RNA甲基化调节因子表达与HCC预后密切相关,有可能作为肿瘤诊断的分子标志物和潜在的治疗靶点。

Objective To explore the relationship between N^(6)-methyladenine(m^(6)A)RNA methylation regulator and prognosis of hepatocellular carcinoma(HCC).Methods The RNA-seq transcriptome data of HCC and normal control samples were downloaded from The Cancer Genome Atlas of the National Cancer Institute.The clinicopathological data of HCC samples were collected.The expression data of 13 kinds of m^(6)A RNA methylation regulators were obtained,including FTO,YTHDC2,YTHDC1,ALKBH5,KIAA1429,METTL3,HNRNPC,YTHDF2,RBM15,YTHDF1,WTAP,MET⁃TL14,and ZC3H13,and then we compared the m^(6)A RNA methylation regulator expression between the hepatocellular car⁃cinoma and normal tissues.Univariate Cox regression analysis and Lasso Cox regression analysis were used to screen out the m^(6)A RNA methylation regulators related to the prognosis of HCC,and we constructed a risk assessment model and ana⁃lyzed the relationship between the risk assessment model and the prognosis of patients with HCC.Results The expres⁃sion levels of FTO,YTHDC2,YTHDC1,ALKBH5,KIAA1429,METTL3,HNRNPC,YTHDF2,RBM15,YTHDF1,and WTAP in the HCC tissues were higher than that of the normal tissues(all P<0.01),but there was no significant differ⁃ence in METTL14 or ZC3H13(both P>0.05).Five m^(6)A RNA methylation regulators,such as YTHDF1,ZC3H13,YTHDF2,METTL3,and KIAA1429,were risk factors for the prognosis of HCC(all P<0.05).The prognosis of patients with high expression of ZC3H13 was good,while that of patients with high expression of YTHDF1,YTHDF2,METTL3 and KIAA1429 was poor.We constructed a prognostic risk assessment model of HCC based on these five m^(6)A RNA methyl⁃ation regulators containing YTHDF1,ZC3H13,YTHDF2,METTL3,and KIAA1429.Then HCC patients were divided in⁃to the high-risk and low-risk patients.The 5-year survival rate of high-risk patients was significantly lower than that of low-risk patients(P<0.05).ROC curve showed that the area under the curve was 0.619 in the risk assessment model.Univar⁃iate and multivariate Cox regression analysis showed that the risk model score was an independent risk factor for the progno⁃sis of HCC patients(P<0.01).Conclusion The expression of m^(6)A RNA methylation regulator is closely related to the prognosis of HCC patients,which would be a molecular marker in tumor diagnosis and a potential therapeutic target.