人恶性T细胞扩增序列1在肾透明细胞癌预后中作用及其与免疫浸润关系

Role of MCTS1in the prognosis of renal clear cell carcinoma and its relationship with immune infiltration

目的探讨肾透明细胞癌组织中的人恶性T细胞扩增序列1(MCTS1/MCT1)表达情况及其与肾透明细胞癌临床病理参数之间的关系,通过各种生物信息学工具预测MCTS1靶基因及进行相关功能分析,为进一步研究MCTS1为靶点的基因治疗提供理论依据。方法从癌症基因组图谱(TCGA)数据库中获取肾透明细胞癌患者的表达谱和临床信息。应用Wilcoxon秩和检验,比较肾透明细胞癌组织和正常肾组织中MCTS1的表达水平。为挖掘潜在的信号通路和生物学功能进行了功能富集分析。免疫细胞浸润采用单样本基因集富集分析。应用UALCAN和MethSURV数据库分析MCTS1的甲基化状态。采用Kaplan-Meier方法和Cox回归分析确定MCTS1的预后价值。构建诺模图预测肾透明细胞癌1、3和5年的总生存率(OS)。采用Log-rank检验对P值进行检验。结果基于HPA数据库分析肾透明细胞癌中MCTS1的组织表达水平,MCTS1在肾透明细胞癌组织中的表达水平高于邻近组织,差异有统计学意义,P<0.001;在不同的亚组中,用Kaplan-Meier方法评估MCTS1表达在肾透明细胞癌患者中的预后价值,结果显示,MCTS1的组织表达水平与M病理分期、组织学类型和年龄增长密切相关,差异有统计学意义,P<0.001;当MCTS1的过度表达时OS显著下降,差异有统计学意义,P<0.001;多因素Cox分析确定MCTS1是OS的独立阴性预后标志,合成了符合指数为0.841的OS诺模图,差异有统计学意义,OR=2.574,95%CI为1.446~4.683,P=0.005。UALCAN和MethSURV数据库分析MCTS1的甲基化状态,MCTS1的低甲基化状态与不良预后相关,肾透明细胞肿瘤组织在启动子处的DNA甲基化水平明显低于正常肾脏组织,差异有统计学意义,P<0.001。单样本基因集富集分析结果显示,MCTS1的过度表达与自然杀伤细胞、辅助性T细胞17、肥大细胞和浆细胞样树突状细胞的免疫细胞浸润水平呈负相关,差异有统计学意义,P<0.001。结论MCTS1高表达是肾透明细胞癌预后的一个独立不利因素,与肾透明细胞癌侵袭性的临床特征和不利的免疫浸润密切相关,为进一步研究MCTS1为靶点的基因治疗提供理论依据。

Objective This study aimed to investigate the expression of human malignant T cell expansion sequence 1(MCTS1/MCT1)in renal clear cell carcinoma tissues and its relationship with clinicopathological parameters of renal clear cell carcinoma,predict MCTS1target genes and performe related functional analysis by various bioinformatics tools,and provide a theoretical basis for further study of MCTS1as a target for gene therapy.Methods In this study,expression profiles and clinical information of patients with renal clear cell carcinoma were obtained from the Cancer Genome Atlas(TCGA)database.The Wilcoxon rank sum test was applied to compare the expression levels of MCTS1in renal clear cell carcinoma tissues and normal kidney tissues.Functional enrichment analysis was performed to tap potential signaling pathways and biological functions.Immune cell infiltration was analyzed by single sample gene set enrichment.The methylation status of MCTS1was analyzed using the UALCAN and MethSURV databases.Kaplan-Meier method and Cox regression analysis were used to determine the prognostic value of MCTS1.And a nomogram was constructed to predict the overall survival of renal clear cell carcinoma at 1-,3-and 5years.Log-rank test was used to test the Pvalue.Results The expression level of MCTS1in renal clear cell carcinoma was analyzed based on Human Protein Atlas(HPA)database,the expression level of MCTS1in renal clear cell carcinoma tissues was higher than that in adjacent tissues,and the difference was statistically significant,P<0.001;the prognostic value of MCTS1expression in patients with renal clear cell carcinoma was assessed by Kaplan-Meier method in different subgroups,and the results showed that the tissue expression level of MCTS1was strongly correlated with M pathological stage,histological type and increasing age,with statistically significant differences,P<0.001;overall survival(OS)was significantly decreased when MCTS1was overexpressed,with statistically significant differences,P<0.001;multivariate Cox analysis identified MCTS1as an independent negative prognostic marker for OS,synthesizing a compliance index of 0.841for the overall survival nomogram,with a statistically significant difference,OR=2.574,95%CI:1.446to 4.683,P=0.005.The UALCAN and MethSURV databases analyzed the methylation status of MCTS1,and hypomethylation status of MCTS1was associated with poor prognosis,and the level of DNA methylation in the promoter of renal clear cell tumor tissue was significantly lower than that of normal renal tissue,with a statistically significant difference(P<0.001).In addition,single-sample gene set enrichment analysis showed that MCTS1overexpression was negatively correlated with the level of immune cell infiltration by natural killer cells,helper T cells17,mast cells,and plasmacytoid dendritic cells,with a statistically significant difference,P<0.001.Conclusion The high expression of MCTS1is an independent unfavorable factor in the prognosis of renal clear cell carcinoma,which is closely related to the aggressive clinical features and unfavorable immune infiltration of renal clear cell carcinoma,providing a theoretical basis for further study of MCTS1as a target for gene therapy.