In normal urothelium, superficial umbrella cells express four major
integral membrane proteins,
uroplakins UPIa, UPIb, UPII, and UPIIIa, which compose urothelial plaques. In the apical plasma membrane, urothelial plaques form microridges. During neoplastic changes, microridges are replaced by microvilli, while
uroplakin expression is retained. We correlated individual
uroplakin expression with apical plasma membrane structure,
cytokeratin 20 expression, and urothelial cell proliferation (Ki-67). Male Wistar rats were treated with 0.05%
N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in
drinking water, which caused flat
hyperplasia with mild dysplasia, low-grade papillary urothelial
carcinoma, invasive low- and high-grade papillary urothelial
carcinoma and invasive
squamous cell carcinoma with extensive keratinization, grade 2. During urothelial
carcinogenesis, UPII expression was the most decreased in all urothelial lesions, while UPIa, UPIb, and UPIIIa expression was differently altered in different types of lesions. Superficial cells were covered with microvilli and ropy ridges, while microridges were disappearing. The expression of
cytokeratin 20 was decreased and limited to superficial urothelial cells. Proliferation indices were increased, except for invasive
squamous cell carcinoma with extensive keratinization. Our results indicate that during urothelial
carcinogenesis the expression of UPII is diminished, suggesting that UPIb/UPIIIa heterodimer can still be formed, while heterodimer UPIa/UPII formation is disrupted. Correlation between decreased level of UPII expression and changed apical plasma membrane structure suggests that diminished expression of UPII hinders the urothelial plaque formation.