Integrative pan-cancer analysis of dipeptidyl peptidase 4 with clinical and in vitro validation in prostate cancer

Background Dipeptidyl peptidase 4 (DPP4) plays diverse physiological roles, but its pan-cancer significance and immunomodulatory functions remain poorly characterized. Methods We performed an integrative pan-cancer analysis of DPP4, incorporating transcriptomic, genomic, and immunogenomic approaches. Differential expression, ceRNA networks, protein interactions, immune infiltration, drug sensitivity, molecular docking, and molecular dynamics were systematically evaluated. Single-cell sequencing analysis, virtual knockout analysis and TIDE analysis were conducted to validate the role of DPP4 in prostate cancer. Further clinical validation was conducted in a prostate cancer cohort (n=97) using immunohistochemistry, Kaplan-Meier survival analysis, and clinicopathological correlation studies were also conducted. DPP4 expression was assessed by qPCR in 22Rv1 and C4–2 cells treated with dasatinib or midostaurin at IC 50 concentrations. Results DPP4 exhibited tumor-specific dysregulation across multiple cancer types. Its expression correlated significantly with patient prognosis, tumor stage, genomic alterations, immune cell composition, and therapeutic response. In prostate cancer, DPP4 was markedly downregulated ( p < 0.001) and higher expression predicted better overall survival ( p < 0.001) and progression-free survival ( p < 0.001). Significant associations were observed with Gleason score ( p = 0.03) and WHO/ISUP grade ( p = 0.03). After dasatinib treatment, DPP4 expression in C4–2 was significantly elevated ( p < 0.001). On the contrary, DPP4 expression in both 22Rv1 and C4–2 was reduced after treatment with midostarin ( p < 0.05). Conclusion Our study establishes DPP4 as a multifaceted pan-cancer biomarker with prognostic significance and immunotherapeutic implications, particularly in prostate cancer.