基于多维数据分析的结直肠癌疾病进展分子靶点与机制解析  

Molecular targets and mechanism analysis of colorectal cancer progression based on multi-dimensional data analysis

作　　者：符文涛 张恬真 杨小宝 赵翰铮 张忠涛[1] Fu Wentao;Zhang Tianzhen;Yang Xiaobao;Zhao Hanzheng;Zhang Zhongtao(Department of General Surgery,Beijing Friendship Hospital,Capital Medical University,State Key Lab of Digestive Health,National Clinical Research Center for Digestive Diseases,Beijing 100050,China;Department of Hernia and Abdominal Wall Surgery,Beijing Chaoyang Hospital,Capital Medical University,Beijing 100043,China)

机构地区：[1]首都医科大学附属北京友谊医院普通外科中心、消化健康全国重点实验室、国家消化系统疾病临床医学研究中心,北京100050 [2]首都医科大学附属北京朝阳医院疝和腹壁外科,北京100043

出　　处：《国际外科学杂志》2025年第3期150-155,I0004,I0005,F0003,共9页International Journal of Surgery

基　　金：国家消化系统疾病临床医学研究中心国家科技支撑计划课题(2015BAI13B09);国家自然科学基金(82101923);北京市医院管理局青年项目(QML20230106)。

摘　　要：目的揭示结直肠癌进展的动态分子特征,筛选驱动疾病发展的关键分子及信号通路,为精准诊疗提供理论依据。方法基于TCGA-CRC数据集(556例结直肠癌样本)及GEO数据库中3个结直肠癌数据集(GSE39582/GSE68468/GSE41258),采用DESeq2筛选结直肠癌的差异表达基因;通过Mfuzz时间序列分析鉴定随肿瘤进展表达持续上调的基因簇;利用clusterProfiler进行功能富集分析,使用STRING在线平台构建蛋白质互作网络,鉴定网络中的关键基因;并结合单细胞测序数据(GSE132465/GSE144735)解析关键基因的细胞来源及细胞间通讯;采用单因素Cox比例风险模型(似然比检验)评估基因预后价值,单细胞测序数据通过Seurat流程中的Wilcoxon秩和检验鉴定差异表达基因。结果时间序列分析鉴定出基因簇4(含186个基因)在结直肠癌Ⅰ~Ⅳ期呈持续上调趋势;功能富集分析显示这些基因显著参与细胞外基质(ECM)重塑及PI3K-Akt、MAPK等信号通路;PPI网络筛选出COL10A1、THBS2、SPP1等10个关键基因,其高表达与患者不良预后显著相关;单细胞测序揭示这些关键基因特异性高表达于成纤维细胞亚群,而SPP1主要富集于巨噬细胞;细胞通讯分析证实THBS2-CD47和SPP1-CD44是介导成纤维细胞-免疫/内皮细胞互作的主要通路。结论ECM相关基因与结直肠癌的进展密切相关,其关键分子THBS2和SPP1可能通过介导THBS2-CD47及SPP1-CD44互作通路,驱动肿瘤微环境中基质-免疫细胞通讯,进而促进结直肠癌进展。Objective:To unveil the dynamic molecular characteristics of colorectal cancer(CRC)progression,identify key molecules and signaling pathways driving disease development,and provide a theoretical basis for precision diagnosis and treatment.Methods:Differentially expressed genes(DEGs)were identified using DESeq2 based on the TCGA-CRC dataset(556 colorectal cancer samples)and three independent validation cohorts from the GEO database(GSE39582,GSE68468,GSE41258).Mfuzz time-series analysiswas applied to identify gene clusters with continuously upregulated expression during tumor progression.Functional enrichment analysis was performed using clusterProfiler,and protein-protein interaction(PPI)networks were constructed via the STRING online platform to pinpoint hub genes.Single-cell sequencing data(GSE132465/GSE144735)were integrated to resolve the cellular origins and intercellular communication of key genes.The prognostic value of genes was assessed using a univariate Cox proportional hazards model(likelihood ratio test),and single-cell sequencing data were analyzed using the Seurat pipeline with Wilcoxon rank-sum test to identify DEGs.Results:Time-series analysis identified Gene Cluster 4(containing 186 genes)with a sustained upregulation trend across CRC stages fromⅠtoⅣ.Functional enrichment revealed these genes were significantly involved in extracellular matrix(ECM)remodeling and pathways such as PI3K-Akt and MAPK signaling.PPI network analysis screened 10 hub genes(COL10A1,THBS2,SPP1,etc.),whose high expression correlated significantly with poor patient prognosis.Single-cell sequencing demonstrated that these hub genes were predominantly expressed in fibroblast subpopulations,while SPP1 was enriched in macrophages.Cell-cell communication analysis confirmed that THBS2-CD47 and SPP1-CD44 were the primary pathways mediating fibroblast-immune/endothelial cell interactions.Conclusion:ECM-related genes are closely associated with the progression of CRC,in which the key molecules THBS2 and SPP1 may drive stromal-imm

关 键 词：结直肠肿瘤 单细胞分析 细胞外基质 

分 类 号：R735.3[医药卫生—肿瘤]