Figure 1.

 Overexpression of DNA methyltransferase (DNMT) 1 protein during multistage urothelial carcinogenesis. (a) Specimen obtained by radical cystectomy for multiple urothelial carcinomas (UCs) of the urinary bladder, bilateral ureters, and prostatic urethra. UCs are clinically remarkable because of their multicentricity and tendency to recur: synchronously or metachronously multifocal UCs often develop in individual patients.^{( 38 )} A possible mechanism for such multiplicity is the “field effect.” Even non‐cancerous urothelia showing no remarkable histological changes obtained from patients with UCs can be considered precancerous, because they may be exposed to carcinogens in the urine. (b) Immunohistochemical examination for DNMT1 and proliferating cell nuclear antigen (PCNA) in tissue specimens. The incidence of nuclear DNMT1 immunoreactivity had already increased in non‐cancerous urothelia showing no remarkable histological changes obtained from patients with UCs (NC), where the PCNA labeling index had not yet increased, compared to that in normal urothelia obtained from patients without UCs (Cont), indicating that DNMT1 overexpression preceded any increase of cell proliferative activity.^{( 56 )} The intensity of nuclear DNMT1 immunoreactivity was further increased in UCs.^{( 56 )}