MCM4作为增殖信号影响肺腺癌的免疫浸润和预后  

MCM4 as a proliferation signal affects immune infiltration and prognosis in lung

作　　者：金燕 许斌[1] 宋启斌[1] JIN Yan;XU Bin;SONG Qibin(Cancer Center,Renmin Hospital of Wuhan University,Wuhan 430060,China)

机构地区：[1]武汉大学人民医院肿瘤中心,武汉430060

出　　处：《临床与病理杂志》2024年第2期169-182,共14页Journal of Clinical and Pathological Research

摘　　要：目的:微小染色体维持蛋白4(minichromosome maintenance protein 4,MCM4)是DNA复制起始和延伸阶段的调控因子。本研究旨在探究肺腺癌(lung adenocarcinoma,LUAD)中MCM4的表达与肿瘤微环境(tumor microenvironment,TME)中免疫细胞和分子的相关性,以及MCM4预测患者免疫治疗敏感性和预后的能力。方法:从癌症基因组图谱(The Cancer Genome Atlas,TCGA)、基因表达综合(Gene Expression Omnibus,GEO)数据库中下载并筛选LUAD患者的转录组数据和临床数据进行分析。其中TCGA数据集的503例患者为训练集,GEO数据集的857例患者为验证集。采用TIMER(Tumor Immune Estimation Resource)数据库对MCM4在正常组织和肿瘤组织中的表达情况进行分析。将LUAD患者肿瘤样本划分为MCM4低表达组和MCM4高表达组,采用R软件分析LUAD患者MCM4表达与总生存期(overall survival,OS)的关系;采用京都基因与基因组数据库(Kyoto Encyclopedia of Genes and Genomes,KEGG)中的基因集进行基因富集分析,筛选与MCM4基因表达相关的生物学过程;采用肿瘤免疫功能障碍与排斥(tumor immune dysfunction and exclusion,TIDE)评分预测患者的免疫治疗的效果;评估LUAD患者TME的免疫评分、基质评分和ESTIMATE(estimation of stromal and immune cells in malignant tumor tissues using expression data)评分,分析MCM4表达与TME中免疫细胞、免疫检查点(immune checkpoint,ICs)之间的关系。收集武汉大学人民医院病理确诊为LUAD的穿刺或者手术切片60张(55张为LUAD的癌组织和癌旁组织,5张为正常肺组织)及临床病理资料,采用免疫组织化学染色法进行临床验证。结果:MCM4基因和蛋白质在肺正常组织和腺癌组织中差异表达。在训练集和验证集中,MCM4低表达组患者的OS均优于MCM4高表达组;MCM4均可以影响LUAD患者的预后;MCM4表达与卵母细胞减数分裂、细胞周期和DNA复制通路显著相关,且MCM4与Ki-67编码基因MKI67和增殖相关基因C1orf112均呈显著正�Objective:Minichromosome maintenance protein 4(MCM4)is a regulator involved in the initiation and elongation stages of DNA replication.This study aims to investigate the correlation between MCM4 expression and immune cells and molecules in the tumor microenvironment(TME)of lung adenocarcinoma(LUAD),and the ability of MCM4 to predict patient sensitivity to immunotherapy and prognosis.Methods:Transcriptome data and clinical data of LUAD patients were downloaded and analyzed from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.The training set comprised 503 patients from the TCGA dataset,while the validation set comprised 857 patients from the GEO dataset.The expression of MCM4 in normal and tumor tissues was analyzed using the tumor immune estimation resource(TIMER)database.LUAD tumor samples were divided into MCM4 low expression and MCM4 high expression groups,and R software was used to analyze the relationship between MCM4 expression and overall survival(OS)of LUAD patients.Gene set enrichment analysis was performed using gene sets from the Kyoto Encyclopedia of Genes and Genomes(KEGG)to identify biological processes related to MCM4 gene expression.The Tumor Immune Dysfunction and Exclusion(TIDE)score was used to predict the efficacy of immunotherapy in LUAD patients.Immune scores,stromal scores,and estimation of stromal and immune cells in malignant tumor tissues using expression data(ESTIMATE)scores were assessed to analyze the relationship between MCM4 expression and immune cells and immune checkpoints(ICs)in the TME.Clinical validation was conducted using immunohistochemical staining on 60 biopsy or surgical specimens diagnosed as LUAD(55 of LUAD cancerous tissues and adjacent tissues,5 of normal lung tissues)from Renmin Hospital of Wuhan University.Results:Differential expression of the MCM4 gene and protein was observed between normal lung tissue and adenocarcinoma tissue.In both the training and validation sets,patients in the MCM4 low expression group had better OS compared to those

关 键 词：微小染色体维持蛋白4 肺腺癌 增殖 免疫抑制 预后 

分 类 号：R734.2[医药卫生—肿瘤]