PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer

Objectives: PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) is induced by hypoxia and is strongly associated with glycolysis. Previously, we reported that PFKFB4 expression level may serve as a predictor of progression in non-muscle-invasive bladder cancer (NMIBC). Here, the role of PFKFB4 in NMIBC and the relationship between PFKFB4 expression and biological behavior in bladder cancer was investigated. Methods: One hundred ninety-three primary NMIBC tissue specimens were analyzed by real-time PCR. Immunohistochemical staining was performed on 77 subsets of tumor samples. The results were compared with clinicopathologic parameters, and the Kaplan-Meier method and a multivariate Cox regression model were used to identify the prognostic value of PFKFB4 for recurrence and progression. Results: The mRNA expression levels of PFKFB4 were significantly higher in patients with high stage carcinoma and multiple tumors as compared to low stage and single tumors (P < 0.05 for each). Kaplan-Meier estimates revealed significant differences in time to recurrence and progression between low- and high-mRNA expression groups (log-rank test, P = 0.015 and 0.003, respectively). Multivariate Cox regression analysis revealed that the level of PFKFB4 expression is an independent predictor of bladder tumor progression (HR, 2.026; 95% Cl, 1.177-3.488; P = 0.011). Immunohistochemical findings were generally concordant with mRNA expression levels. Conclusions: PFKFB4 has an important role in the progression of NMIBC, and may serve as a useful prognostic indicator for bladder cancer progression. Crown Copyright (C) 2012 Published by Elsevier Inc. All rights reserved.