Dipeptidyl peptidase-4 (DPP4) has been implicated in tumor progression, yet its role in clear cell renal cell carcinoma (KIRC) remains poorly understood. This study aimed to comprehensively investigate the expression profile, prognostic significance, and functional mechanisms of DPP4 in KIRC through integrated bioinformatics analysis and experimental validation. Bioinformatics tools (GEPIA, UALCAN, Kaplan-Meier Plotter, STRING, Metascape, TIMER, cBioPortal) were employed to analyze DPP4 expression patterns, promoter methylation status, genetic alterations, immune infiltration characteristics, and clinical correlations using TCGA-KIRC datasets. In vitro experimental validation included qPCR, Western blot, CCK-8 proliferation assays, wound healing assays, and Transwell migration/invasion assays in KIRC cell lines (Caki-1, ACHN, 786-O) and normal renal tubular epithelial cells (HK-2) to elucidate DPP4’s functional roles in tumor progression. Bioinformatics analysis revealed significant upregulation of DPP4 in KIRC tissues compared to normal controls (P < 0.001), with elevated expression strongly correlating with advanced pathological stage (P < 0.001) and poorer overall survival (P < 0.001). Epigenetic analysis demonstrated promoter hypermethylation and genetic alterations (2.2% mutation frequency) associated with KIRC progression. Functional enrichment analysis linked DPP4 to immune regulation (particularly TNF signaling pathway) and epithelial-mesenchymal transition (EMT) processes. Immune profiling via TIMER showed positive correlations between DPP4 expression and infiltration of immunosuppressive cells (Tregs, M2 macrophages). Experimental validation confirmed DPP4 overexpression in KIRC cells, while its knockdown significantly inhibited cellular proliferation, migration, and EMT progression, as evidenced by upregulated E-cadherin and downregulated N-cadherin, Vimentin, and SNAIL expression. A prognostic nomogram incorporating DPP4 expression and clinical parameters demonstrated robust predictive accuracy (AUC = 0.640). DPP4 promotes KIRC progression through dual mechanisms involving EMT activation and immune microenvironment modulation, serving as both an independent prognostic biomarker and a potential therapeutic target. This study provides comprehensive multi-omics insights into the oncogenic role of DPP4 in KIRC, effectively bridging computational predictions with experimental validation.
Luo et al. (Mon,) studied this question.