BERKELEY, CA (UroToday.com) - The urothelium has the capacity to metabolize certain procarcinogens into genotoxic metabolites.[1]
The glutathione-S-transferases (GSTs) play a major role in the cellular metabolism and detoxification of various xenobiotics.[2,3] Several types of allelic variation have been identified within GST classes. These include GSTM1-null and GSTT1-null, which confer impaired catalytic activity.[4] Although research has suggested that polymorphisms in GST are associated with the risk of developing BC, these findings remain contentious and differences have been reported between ethnic groups.[5,6,7] The aim of the present study was to investigate possible correlations between the expression of GSTM1 and GSTT1 and BC.Tumor samples and matched normal mucosae were obtained from 34 patients. Genomic DNA was used to analyze GSTM1 and GSTT1 genotypes using multiplex polymerase chain reaction (PCR). GSTM1 and GSTT1 mRNA levels were measured using real time reverse transcriptase polymerase chain reaction (RT-PCR).
A GSTT1-positive genotype was detected in 77.8% of the high grade BC specimens and 36.0% of the low grade BC specimens (p=0.031). The mRNA expression of GSTM1 and GSTT1 was higher in BC tissues with positive genotypes than in those with null genotypes. However, this difference was only statistically significant for the GSTT1 genotype group (p=0.003). A comparison was made between the mRNA expression of GSTM1 and GSTT1 in the 34 BC specimens and that in matched normal mucosae. GSTM1 mRNA expression was lower in tumor tissue than in normal tissue (p=0.015). GSTT1 mRNA expression was significantly higher in tumor tissue than in matched normal mucosae (p=0.041). GSTT1 mRNA expression was higher in muscle invasive bladder cancer (MIBC) and high-grade specimens than in non-muscle invasive bladder cancer (NMIBC) and lower grade specimen (p=0.017 and p=0.008, respectively).
In the present study, GSTT1 expression was significantly higher in BC tissues with GSTT1-positive genotypes than in those with GSTT1-null genotypes. This indicates that GSTT1 genotype was correlated with GSTT1 expression. In addition, GSTT1 mRNA expression was significantly higher in tumor tissues than in matched normal tissues. These findings suggest that GSTT1 expression may be upregulated during bladder tumorigenesis. Tumor GSTT1 mRNA expression was correlated with tumor stage and grade, and showed a tendency toward a positive correlation with tumor aggressiveness. These findings are in accordance with those of Simic et al..[8] Only one previous study has investigated GSTM1 and GSTT1 genotypes and their expression in BC.[8] In this study, enzymatic analysis of GST expression in 24 BC specimens indicated that mean GSTT1 enzyme activity was significantly increased in tumor tissue compared with matched normal mucosa. However, unlike the quantification methods used in the present study, detection of enzyme activity is impractical in a clinical setting. Another difference between the two studies was the tumor stage of the investigated specimens. In the present sample, tumor stage was equally distributed, whereas in the study by Simic et al., high-stage tumors were more prevalent.
In conclusion, GSTM1 expression was lower in primary BC tumor tissues than in matched normal tissues. However, GSTT1 mRNA expression was enhanced in tumor tissues and was correlated with characteristics of aggressive of BC. GSTT1 activity may play an important role in tumorigenesis and disease progression in patients with BC.
References:
- Thier R, Golka K, Bruning T, Ko Y, Bolt HM: Genetic susceptibility to environmental toxicants: The interface between human and experimental studies in the development of new toxicological concepts. Toxicol Lett 2002;127:321-327.
- Pinkus LM, Ketley JN, Jakoby WB: The glutathione s-transferases as a possible detoxification system of rat intestinal epithelium. Biochem Pharmacol 1977;26:2359-2363.
- Chasseaud LF: The role of glutathione and glutathione s-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res 1979;29:175-274.
- Hayes JD, Strange RC: Glutathione s-transferase polymorphisms and their biological consequences. Pharmacology 2000;61:154-166.
- Kim WJ, Lee HL, Lee SC, Kim YT, Kim H: Polymorphisms of n-acetyltransferase 2, glutathione s-transferase mu and theta genes as risk factors of bladder cancer in relation to asthma and tuberculosis. J Urol 2000;164:209-213.
- Bell DA, Taylor JA, Paulson DF, Robertson CN, Mohler JL, Lucier GW: Genetic risk and carcinogen exposure: A common inherited defect of the carcinogen-metabolism gene glutathione s-transferase m1 (gstm1) that increases susceptibility to bladder cancer. J Natl Cancer Inst 1993;85:1159-1164.
- Katoh T, Inatomi H, Kim H, Yang M, Matsumoto T, Kawamoto T: Effects of glutathione s-transferase (gst) m1 and gstt1 genotypes on urothelial cancer risk. Cancer Lett 1998;132:147-152.
- Simic T, Mimic-Oka J, Savic-Radojevic A, Opacic M, Pljesa M, Dragicevic D, Djokic M, Radosavljevic R: Glutathione s-transferase t1-1 activity upregulated in transitional cell carcinoma of urinary bladder. Urology 2005;65:1035-1040.
Written by:
Yun-Sok Ha, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
GSTT1: A marker of the aggressiveness of bladder cancer - Abstract
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