Exploring XDH expression as a prognostic marker for urothelial carcinoma

PURPOSE: Xanthine dehydrogenase (XDH) serves as a key enzyme in purine metabolism and plays a significant role in carcinogenesis. However, the clinical significance of XDH in urothelial carcinoma (UC) progression remains unclear. Using a transcriptomic UC database (GSE32894), we found that among the genes related to XDH activity (GO:0004854), XDH was significantly downregulated during UC progression. Therefore, we aimed to assess the prognostic value of XDH immunoexpression in urinary bladder UC (UBUC) and upper tract UC (UTUC) patients. METHODS: Immunohistochemical staining for XDH was performed on 340 UTUC and 295 UBUC specimens. The association of XDH expression with clinicopathological features and patients' outcomes, including disease-specific survival (DSS) and metastasis-free survival (MFS), was analyzed using Pearson's chi-square test, Kaplan-Meier analysis, and multivariate Cox proportional hazards model to identify independent prognosticators. RESULTS: Low XDH expression was significantly associated with high tumor stage, nodal metastasis, high tumor grade, perineural invasion, vascular invasion, and a high mitotic rate (all P < 0.01). Kaplan-Meier survival curves showed that low XDH expression was associated with poor DSS and MFS (both p < 0.001). After adjusting for the standard pathological parameters, XDH expression status was an independent prognostic factor for DSS and MFS in UBUC and UTUC (all P < 0.01) in the multivariate analysis model. To associate XDH with potential functions in UC, gene co-expression examination was performed using the GO classification system. XDH upregulation was linked to pyroptosis and desmosomes. CONCLUSION: Low XDH expression correlates with aggressive pathological features and poor oncological outcomes, indicating its prognostic and therapeutic significances in patients with UC.