Abstract
The urea transporter UT-B is widely expressed and has been studied in erythrocyte, kidney, brain and intestines. Interestingly, UT-B gene has been found more abundant in bladder than any other tissue. Recently, gene analyses demonstrate that SLC14A1 (UT-B) gene mutations are associated with bladder cancer, suggesting that urea transporter UT-B may play an important role in bladder carcinogenesis. In this study, we examined UT-B expression in bladder cancer with human primary bladder cancer tissues and cancer derived cell lines. Human UT-B has two isoforms. We found that normal bladder expresses long form of UT-B2 but was lost in 8 of 24 (33%) or significantly downregulated in 16 of 24 (67%) of primary bladder cancer patients. In contrast, the short form of UT-B1 lacking exon 3 was detected in 20 bladder cancer samples. Surprisingly, a 24-nt in-frame deletion in exon 4 in UT-B1 (UT-B1Δ24) was identified in 11 of 20 (55%) bladder tumors. This deletion caused a functional defect of UT-B1. Immunohistochemistry revealed that UT-B protein levels were significantly decreased in bladder cancers. Western blot analysis showed a weak UT-B band of 40 kDa in some tumors, consistent with UT-B1 gene expression detected by RT-PCR. Interestingly, bladder cancer associate UT-B1Δ24 was barely sialylated, reflecting impaired glycosylation of UT-B1 in bladder tumors. In conclusion, SLC14A1 gene and UT-B protein expression are significantly changed in bladder cancers. The aberrant UT-B expression may promote bladder cancer development or facilitate carcinogenesis induced by other carcinogens.
Highlights
Urea is the major end product of nitrogen metabolism and is excreted by the kidney
We designed two pairs of UT-B primers to amplify UT-B2 and UT-B1 from normal human bladder tissue cDNAs purchased from BioChain
A single N-glycosylation site was identified at Asn 211 in the UT-B protein (Shayakul et al, 2013).We previously reported that cell membrane UT-A1 and UT-A3 are localized in lipid raft microdomains and glycosylation facilitates UT-A1 lipid raft distribution in lipid rafts (Chen et al, 2011; Su et al, 2012)
Summary
Urea is the major end product of nitrogen metabolism and is excreted by the kidney. Due to its small molecular size (∼60 Da) and water solubility, urea has been considered to be freely permeable across the cell membrane for over 30 years (Sands, 2003a, 2007). As a highly polar molecule, urea permeability across lipid bilayers is very low. There are two types of urea transporters, UT-A and UT-B, encoded by the solute carrier family SLC14A2 and SLC14A1 genes, respectively. These genes share a high degree of homology and are aligned in tandem at chromosome 18q12.3 in humans. UT-A urea transporters are mainly expressed in kidney
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