CDH1, CAV1, NR3C1, and ZEB1 are Potential Biomarkers in Colorectal Cancer Drug Resistance and Prognosis.

Abstract

IntroductionColorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with drug resistance and poor prognosis significantly limiting treatment efficacy. To address this unmet clinical need, this study aimed to screen potential biomarkers for CRC drug resistance and prognosis through integrated bioinformatics analysis and clinical sample validation.MethodsWe analyzed Gene Expression Omnibus (GEO) database GSE153412 to screen differentially expressed genes (DEGs) between 5-fluorouracil (5-FU)-resistant and sensitive CRC cells (|log2FC| > 1.0, adj P < 0.05). Gene set enrichment analysis (GSEA) was used for pathway enrichment, Weighted gene co-expression network analysis (WGCNA) to identify resistance-related modules (correlation > 0.7, P < 0.01), and Protein-protein interaction (PPI) networks to screen hub genes. Their prognostic value was evaluated in TCGA-COAD, along with IC50 correlation. Finally, qPCR verified biomarker expression in clinical CRC samples.ResultsThere were altogether 1033 DEGs screened. Through GSEA, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms enriched by the DEGs were obtained. By PPI network construction, hub genes were screened. In TCGA-COAD datasets, CAV1 (P = 0.018), CDH1 (P = 0.049), CXCL8 (P = 0.00068), CD24 (P = 0.00017), NR3C1 (P = 0.016), and ZEB1 (P = 0.042) were also related to CRC prognosis. The correlation analysis of key genes and drug resistance suggested the emergence of CDH1, CAV1, NR3C1, and ZEB1, which was also examined by clinical data validation.ConclusionIntegrated bioinformatics and clinical validation analyses identified CDH1, CAV1, NR3C1, and ZEB1 as key biomarkers for CRC. These genes were significantly associated with 5-FU resistance and CRC prognosis, as supported by their dysregulated expression in clinical samples, highlighting their mechanistic roles in the CRC drug resistance pathways.