Serum xanthine oxidoreductase and oxidative stress are associated with bladder cancer: a case-control study from Jordan

Xanthine oxidoreductase (XOR) is an oxidant enzyme that exists mainly in two distinct forms: the dehydrogenase form [xanthine dehydrogenase (XDH)] and the oxidized form [xanthine oxidase (XO)]. XO might contribute to tumorigenesis through direct metabolic activation of carcinogens and indirect generation of free radicals. Oxidative stress is one of the leading causes of bladder cancer (BC). Smoking and genetic susceptibility are also linked to oxidative stress and BC. This study investigated the association between XO serum levels and XOR genetic polymorphisms with BC. A case-control study was conducted among 109 BC patients and 109 controls matched by age, gender, body mass index, and smoking status. Serum levels of XO and 8-hydroxy-2'-deoxyguanosine (8-OhdG) were measured using ELISA, while thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC) were assessed using colorimetric assays. XOR single nucleotide polymorphisms were analyzed via tetra-primer ARMS-PCR. XO levels were significantly higher in BC patients than in controls [(5.11 ± 0.28 vs 3.83 ± 0.23) ng/ml, respectively (p < 0.0006)]. Among smokers, XO levels were also elevated in BC cases compared with controls [(5.29 ± 0.35 vs 3.41 ± 0.28) ng/ml, respectively (p < 0.0001)]. Oxidative stress biomarkers were elevated in BC patients compared with controls: 8-OHdG (19.39 ± 1.37 vs 16.32 ± 1.37 nmol/l), PC (8.88 ± 0.56 vs 4.42 ± 0.56) nmol/mg of protein, and TBARS (4.23 vs 3.15) µmol/ml, respectively (p < 0.05). Haplotype analysis showed that TGTCA, TGTA, TGA, and GTA were more frequent in BC patients and associated with increased BC status [4.17 (1.16-15.00), 1.84 (1.11-3.05), 1.62 (1.01-2.60), and 1.66 (1.02-2.71) fold increase in risk, respectively (p < 0.05)]. Elevated XO and oxidative stress markers are associated with BC, supporting their role in BC pathogenesis. Our findings suggest that they may act as potential diagnostic or therapeutic targets. However, mechanistic studies are required to clarify whether XO/oxidative stress markers contribute directly to carcinogenesis or reflects general redox imbalance in malignancy. Specific XOR haplotypes might serve as biomarkers for BC.