生物信息学方法分析CLDN9基因在子宫内膜癌中表达对生存率的影响-东南大学学报医学版

生物信息学方法分析CLDN9基因在子宫内膜癌中表达对生存率的影响

单位：1. 同济大学附属杨浦医院临床研究与转化医学中心, 上海 200120;
2. 同济大学附属第一妇婴保健院生殖医学中心, 上海 200120

分类号：R737.33

出版年·卷·期（页码）：2023·42·第二期（169-180）

摘要：

目的:通过生物信息学方法分析子宫内膜癌(UCEC)中与肿瘤微环境(TME)相关的核心基因。方法:从UCSC Xena数据库下载TCGA数据库中的UCEC基因表达和临床数据。通过R软件中的ESTIMATE包计算样本的免疫细胞与基质细胞综合评分(ESTIMATE Score),将样本分为ESTIMATE Score高、低两组,分析组间差异基因(DEGs),对DEGs进行富集分析。再对DEGs进行加权基因共表达网络分析(WGCNA),得到核心基因模块。分析核心模块基因在肿瘤和正常组织中的表达情况,结合DEGs在UCEC及子宫内膜组织中的表达水平及差异程度选取研究的目的基因。通过String数据库构建目的基因的蛋白互作网络,分析目的基因的表达与UCEC的病理特征、生存预后、TME之间的相关性。对目的基因进行GSEA富集分析,分析与目的基因表达相关的生物学通路。结果:ESTIMATE Score高、低组间共有1 068个DEGs,GO/KEGG富集分析结果显示DEGs主要富集在细胞免疫反应、细胞因子及受体结合等相关生物学通路上。对DEGs进行WGCNA聚类分析得到与UCEC的病理特征、生存预后显著相关的由77个DEGs组成的基因模块。模块基因中的CLDN9在UCEC与正常内膜组织中存在显著表达差异,且随着UCEC的病理特征的恶化,CLDN9的表达呈上升趋势,同时CLDN9的表达与患者的生存呈负相关。String数据库预测了10个可能与CLDN9存在交互作用的蛋白分子。GSEA富集分析结果显示,CLDN9的表达与CD8⁺T细胞免疫、KRAS基因调节的信号通路、异生代谢、脂肪酸代谢等通路密切相关。在UCEC的TME中,CLDN9的表达与CD8⁺ T细胞等免疫细胞的浸润水平存在着负相关。结论:本研究分析鉴定了与UCEC病理特征、生存预后、TME相关的DEGs,并从中进一步分析鉴定出了与UCEC的病理分期、免疫浸润、患者生存率密切相关的CLDN9,为UCEC的诊断治疗提供了新思路。

Objective: To analyze and identify core genes associated with tumor microenvironment(TME) in uterine corpus endometrial cancer(UCEC) by using bioinformatics methods.Methods: UCEC gene expression and clinical data were downloaded from UCSC Xena database. The ESTIMATE package in R software was used to calculate the ESTIMATE score of the sample, the sample were divided into high and low groups through the ESTIMATE score, and differentialy expressed genes(DEGs) were enrichment analyzed. The core gene modules were obtained by WGCNA cluster analysis of DEGs. The expression of core module genes in tumor and normal tissues were analyzed, and the target genes for the study according to the expression level and difference degree of DEGS in UCEC and endometrial tissues were selected. The protein interaction network of target genes was constructed through String database.The correlation between target gene expression and UCEC pathological features, survival prognosis and TME has been analyzed. GSEA enrichment analysis was carried out for the target gene to analyze the biological pathway related to the expression of the target gene. Results: A total of 1 068 DEGs were obtained by analyzing the differential genes between groups with high and low ESTIMATE score. The GO/KEGG enrichment analysis showed that DEGs were mainly enriched in the cellular immune response, cytokine and receptor binding and other related biological pathways.WGCNA cluster analysis of DEGs showed that there were 77 DEGs gene modules which were significantly related to the pathological characteristics and survival prognosis of UCEC.CLDN9 in the modular gene had significant difference in expression between UCEC and normal endometrial tissue.With the deterioration of the pathological characteristics of UCEC, the expression of CLDN9 showed an upward trend, and the expression of CLDN9 was negatively correlated with the survival of tumor patients.The String database predicted 10 protein molecules that may interact with CLDN9.GSEA enrichment analysis showed that the expression of CLDN9 was closely related to CD8⁺T cell immunity, KRAS gene regulation, metametabolism, fatty acid metabolism and other pathways.In TME of UCEC, the expression of CLDN9 had a negative relationship with the infiltration level of CD8⁺ T Cells and other immune cells. Conclusion: This study analyzed and identified the DEGs related to the pathological characteristics, survival prognosis and TME of UCEC, and found that CLDN9 may become a new target for diagnosis, tumor immunotherapy and survival prediction of UCEC.

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