High Ubiquitin-like Protein 3 Expression Is Associated With Prolonged Recurrence-free Survival in Non-muscle-invasive Bladder Cancer

Background/aim Current clinicopathological factors inadequately capture the biological heterogeneity of non-muscle-invasive bladder cancer (NMIBC). This study investigated the prognostic significance of ubiquitin-like protein 3 (UBL3), a molecule involved in extracellular vesicle sorting and immune regulation, in NMIBC. Materials and methods Following an exploratory analysis of public RNA-sequencing databases, we evaluated tissue samples from patients who underwent transurethral resection for primary NMIBC. A discovery cohort (n=37) was assessed for UBL3 mRNA via qRT-PCR and protein expression via immunohistochemistry (IHC) quantified using digital H-scores (QuPath). A separate internal validation cohort (n=192) was subsequently evaluated by IHC. The primary endpoint was recurrence-free survival (RFS). Results The database analysis indicated that high UBL3 expression was associated with longer RFS in early-stage bladder cancer. In the discovery cohort, higher UBL3 mRNA levels were associated with prolonged RFS [hazard ratio (HR)=0.33, p=0.004]. mRNA levels also were associated with digital H-scores (ρ=0.39, p=0.018). In the separate internal validation cohort, elevated UBL3 protein expression was associated with a reduced risk of recurrence. A multivariable Cox regression confirmed that a higher UBL3 H-score (HR=0.95 per 10-point increase, p=0.023), alongside a negative preoperative urine cytology and immediate intravesical chemotherapy, remained independently associated with RFS. Conclusion Elevated UBL3 expression was associated with prolonged RFS in patients with NMIBC following transurethral resection of bladder tumor. While UBL3 has potential as a prognostic biomarker, establishing its definitive clinical utility will require mechanistic investigations and validation across independent, multicenter cohorts.