CMTM2甲基化变化与肝细胞癌患者预后的关联性

The correlation between CMTM2 methylation and prognosis of patients in hepatocellular carcinoma

目的探讨CMTM2甲基化与其基因表达及肝细胞癌患者预后的关联性。方法从癌症基因组图谱(The Cancer Genome Atlas,TCGA)和基因表达谱(Gene Expression Omnibus,GEO)数据库获取CMTM2甲基化及基因表达数据,应用R软件和Perl脚本进行数据整合,对肝癌组织与癌旁组织中的CMTM2甲基化和基因表达进行相关性分析,并比较不同CMTM2甲基化水平肝癌患者预后的差异。应用Mass ARRAY核酸质谱技术分析DNA甲基化抑制剂处理前后肝癌细胞中CMTM2甲基化水平的变化,体外细胞验证DNA甲基化对CMTM2基因表达的影响。结果CMTM2在肝癌组织中表达水平低于癌旁组织(P=0.0075),而CMTM2在肝癌组织中甲基化程度高于癌旁组织(P<0.001)。Kaplan-Meier生存分析显示,CMTM2高甲基化患者的总生存期(HR=1.4548,95%CI:1.0223~2.0705,P=0.037)与无病生存期(HR=1.5148,95%CI:1.0953~2.0948,P=0.012)均缩短。CMTM2在启动子区域cg07153665位点发生高甲基化,使用DNA甲基化抑制剂处理后,cg07153665位点甲基化水平降低,而CMTM2表达水平上调。结论cg07153665甲基化位点通过调控CMTM2的表达影响肝癌患者的总生存期和无病生存期,提示cg07153665甲基化位点可能是肝癌患者潜在的预后评估指标及治疗靶点。

Objective To determine the relationship between the methylation of the CMTM2 gene,its expression,and the prognosis of patients with hepatocellular carcinoma(HCC).Methods The CMTM2 methylation and gene expression data were obtained from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.R software and Perl script were used to integrate the data.Correlation analysis was performed on the methylation and expression of CMTM2 in HCC and adjacent tissues.The differences in prognosis among HCC patients with varying levels of CMTM2 methylation were assessed.The Mass ARRAY nucleic acid mass spectrometry was used to detect the changes of CMTM2 methylation levels in HCC cells before and after treatment with DNA methylation inhibitors to verify the effect of DNA methylation on CMTM2 gene expression in vitro.Results Expression of the CMTM2 gene was found to be lower in HCC tissues than in adjacent tissues(P=0.0075),and CMTM2 methylation was higher in HCC tissues than in adjacent tissues(P<0.001).Kaplan-Meier survival analysis showed that patients with CMTM2 hypermethylation had shorter overall survival(HR=1.4548,95%CI:1.0223-2.0705,P=0.037)and disease-free survival(HR=1.5148,95%CI:1.0953-2.0948,P=0.012).The CMTM2 gene was hypermethylated at the cg07153665 site in the promoter region.Treatment with DNA methylation inhibitors significantly reduced the methylation level at the cg07153665 site,while the CMTM2 expression level was significantly upregulated.Conclusions Hypermethylation at the cg07153665 site affects the overall survival and disease-free survival of hepatocellular carcinoma patients by regulating the expression of CMTM2,suggesting that cg07153665 may be a potential prognostic assessment indicator and therapeutic target for hepatocellular carcinoma patients.