Expression of RFC/SLC19A1 is associated with tumor type in bladder cancer patients

Abstract

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer. In Egypt, the pattern of bladder cancer is unique in that both the transitional and squamous cell types prevail. Despite much research on the topic, it is still difficult to predict tumor progression, optimal therapy and clinical outcome. The reduced folate carrier (RFC/SLC19A1) is the major transport system for folates in mammalian cells and tissues. RFC is also the primary means of cellular uptake for antifolate cancer chemotherapeutic drugs, however, membrane transport of antifolates by RFC is considered as limiting to antitumor activity. The purpose of this study was to compare the mRNA expression level of RFC/SLC19A1 in urothelial and non-urothelial variants of bladder carcinomas. Quantification of RFC mRNA in the mucosa of 41 untreated bladder cancer patients was performed using RT-qPCR. RFC mRNA steady-state levels were ∼9-fold higher (N = 39; P<0.0001) in bladder tumor specimens relative to normal bladder mRNA. RFC upregulation was strongly correlated with tumor type (urothelial vs. non-urothelial; p<0.05) where median RFC mRNA expression was significantly (p<0.05) higher in the urothelial (∼14-fold) compared to the non-urothelial (∼4-fold) variant. This may account for the variation in response to antifolate-containing regimens used in the treatment of either type. RFC mRNA levels were not associated with tumor grade (I, II and III) or stage (muscle-invasive vs. non-muscle invasive) implying that RFC cannot be used for prognostic purposes in bladder carcinomas and its increased expression is an early event in human bladder tumors pathogenesis. Further, RFC can be considered as a potential marker for predicting response to antifolate chemotherapy in urothelial carcinomas.

Figure 1. mRNA expression of RFC in 39 human biopsy samples relative to the calibrator (A–E).

Solid horizontal lines demonstrate the median of each individual group. All data are shown as the ratio between the target gene and beta-actin. *P-value, non-parametric, Mann-Whitney or Kruskal-Wallis tests. BA, Bilharizal-associated.

Figure 2. RFC is a double-edged weapon.

A diagram depicting the proposed double-edged role of RFC in cancer chemotherapy. Increased expression is predictive of antifolates (MTX) transport. At the same time, increased expression of RFC will lead to folate pool size expansion forcing a negative feedback inhibition on the uptake of antifolates.