Abstract
Although, increased oxidative stress and hypomethylation of long interspersed nuclear element-1 (LINE-1) associate with bladder cancer (BCa) development, the relationship between these alterations is unknown. We evaluated the oxidative stress and hypomethylation of the LINE-1 in 61 BCa patients and 45 normal individuals. To measure the methylation levels and to differentiate the LINE-1 loci into hypermethylated, partially methylated and hypomethylated, peripheral blood cells, urinary exfoliated cells and cancerous tissues were evaluated by combined bisulfite restriction analysis PCR. The urinary total antioxidant status (TAS) and plasma protein carbonyl content were determined. The LINE-1 methylation levels and patterns, especially hypomethylated loci, in the blood and urine cells of the BCa patients were different from the levels and patterns in the healthy controls. The urinary TAS was decreased, whereas the plasma protein carbonyl content was increased in the BCa patients relative to the controls. A positive correlation between the methylation of LINE-1 in the blood-derived DNA and urinary TAS was found in both the BCa and control groups. The urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content provided the best diagnostic potential for BCa prediction. Based on post-diagnostic samples, the combination test improved the diagnostic power to a sensitivity of 96% and a specificity of 96%. In conclusion, decreased LINE-1 methylation is associated with increased oxidative stress both in healthy and BCa subjects across the various tissue types, implying a dose-response association. Increases in the LINE-1 hypomethylation levels and the number of hypomethylated loci in both the blood- and urine-derived cells and increase in the oxidative stress were found in the BCa patients. The combination test of the urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content may be useful for BCa screening and monitoring of treatment.
Highlights
Carcinogenesis of the urinary bladder is complex because both genetic mutations and epigenetic alterations play important roles
The methylation level of long interspersed nuclear element-1 (LINE-1) was measured in DNA derived from peripheral blood, urinary exfoliated cells and cancerous tissues
The percentage of uCuC loci in the peripheral blood cells and urinary exfoliated cells of the bladder cancer (BCa) patients was significantly greater than the controls (P = 0.013 and,0.001, respectively) (Fig. 2C and 2D)
Summary
Carcinogenesis of the urinary bladder is complex because both genetic mutations and epigenetic alterations play important roles. Inflammation and oxidative stress critically contribute to development of bladder cancer (BCa) [1,2,3]. ROS directly damages the cellular DNA and promotes tumor development through genetic mutations and through epigenetic alterations [7]. Common epigenetic alterations in human cancers include global hypomethylation and regional (site-specific CpG island promoter) hypermethylation of the tumor suppressor genes [8,9]. Hypomethylation of the cancer genome occurs on the repetitive sequences and retrotransposable elements [10], which accelerates the genomic instability [10,11,12,13] and alters gene expression [14]. The best characterized and most abundant retrotransposon in the mammalian genome is the long interspersed nuclear element-1 (LINE-1 or L1), and it is known that LINE-1 hypomethylation is associated with many malignancies [15,16]
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