The expression significance and non-invasive detection of REEP6 and REEP5 in prostate cancer

Prostate cancer remains one of the most common malignancies in men. The diagnostic specificity of prostate-specific antigen is limited, and additional non-invasive biomarkers are needed. This study investigated the expression and clinical relevance of receptor expression-enhancing protein 5 (REEP5) and receptor expression-enhancing protein 6 (REEP6) in prostate cancer and assessed their potential as urinary biomarkers.

Urinary REEP5 and REEP6 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in patients with prostate cancer, benign prostatic hyperplasia, urothelial carcinoma, and clear-cell renal cell carcinoma. Immunohistochemistry was performed on prostate cancer tissues, adjacent non-tumour prostate tissues, urothelial carcinoma tissues, and clear-cell renal cell carcinoma tissues. Urinary proteomic analysis was also used for cross-disease comparison. Associations with clinicopathological features and survival outcomes were evaluated using chi-square testing, Spearman's correlation coefficient for ranked data (Spearman's ρ), Kaplan-Meier analysis, and Cox proportional hazards regression model (Cox regression model).

Urinary REEP6 and REEP5 concentrations were significantly higher in the prostate cancer group than in the other disease groups. The mean concentrations of REEP6 and REEP5 in prostate cancer urine were 0.504 ± 0.052 ng/mL and 0.338 ± 0.031 ng/mL, respectively (both P < 0.0001 versus the comparator groups). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of urinary REEP5 and REEP6, which exhibited numerical sensitivity and specificity of 100% for distinguishing prostate cancer from the comparator groups; notably, this seemingly perfect diagnostic performance should be interpreted with extreme caution due to the limited sample size of the control cohort.In tissue analysis, REEP6 showed a positivity rate of 91.2% in prostate cancer and 10.0% in normal prostate tissue, corresponding to a sensitivity of 91.2% and a specificity of 90.0%. REEP5 showed high sensitivity (98.9%) but low specificity (10.0%) in tissue immunohistochemistry. High REEP6 expression was positively correlated with tissue PSA expression (r = 0.219, P = 0.037). Kaplan-Meier analysis showed that high REEP6 expression was associated with longer progression-free survival [(75.650 ± 5.288) months versus (41.255 ± 4.068) months, P = 0.034]. For cancer-specific survival, high REEP6 expression showed a non-significant trend toward longer survival [(79.420 ± 4.156) months versus (51.705 ± 5.417) months, P = 0.067]. Multivariate Cox regression indicated that high REEP6 expression was an independent factor associated with progression-free survival (HR = 0.270, 95% CI 0.074-0.983, P = 0.047).

REEP5 and REEP6 are significantly upregulated in urine and tissue samples from patients with prostate cancer. REEP6 showed higher tissue specificity and prognostic relevance, whereas REEP5 showed high sensitivity but limited tissue specificity. These preliminary findings suggest that urinary REEP5 and REEP6, especially REEP6, may serve as potential exploratory candidate biomarkers for non-invasive auxiliary diagnosis of prostate cancer.Larger prospective studies with independent validation cohorts are required.