Integrated analysis of tissue-exosome Co--differentially expressed genes and their role in diagnosis and pathogenesis of colon cancer

Objective This study aimed to systematically identify co-differentially expressed genes (co-DEGs) by integrating transcriptomic data from colon cancer tissues and circulating exosomes, and to elucidate their roles in pathogenesis and diagnostic potential. Methods We retrieved colon cancer tissue transcriptomes from TCGA-COAD (n = 288) and GTEx normal colon controls (n = 308), and plasma-derived exosome profiles from exoRbase (n = 259 tumor vs 244 control). Differential expression analysis identified 3013 tissue DEGs and 786 exosome DEGs. The intersection of the two sets of DEGs yielded tissue-exosome co-DEGs. Functional annotation, protein-protein interaction (PPI) network construction via STRING, hub gene prioritization using three CytoHubba algorithms (Betweenness, Bottleneck, EcCentricity), and Gene Set Enrichment Analysis (GSEA) were performed. ROC analysis evaluated diagnostic performance using independent GEO validation cohorts. Results The 44 co-DEGs, included 26 upregulated genes (e.g., MMP9 , CDKN3 , CKS2 , histone clusters) and 18 downregulated genes (e.g., PKHD1L1 , KRT1 , ITGB3 , JAM3 ). GSEA revealed significant enrichment in cellular senescence (NES=2.426, FDR<0.001), senescence-associated secretory phenotype (SASP, NES=1.976, FDR<0.001), and immune signaling pathways (e.g., cytokine signaling, NES=1.885, FDR<0.001). Four consensus hub genes ( H3C12 , MMP9 , IFNG , CDKN3 ) were identified by overlapping top 10 genes from three CytoHubba algorithms, with CDKN3 achieving strong diagnostic potential (high accuracy, AUC values >0.9) in validation cohorts. Conclusions Our tissue-exosome co-validation framework isolates a robust 44-gene signature reflecting authentic tumor-derived signals. The four hub genes, particularly CDKN3 , serve as high-fidelity diagnostic biomarkers and key mediators of exosome-mediated senescence-immune reprogramming, offering therapeutic targets for precision oncology in colon cancer.