To explore the cell cycle regulatory mechanism in bladder
carcinogenesis promoted by
terephthalic acid calculi (TPA-
calculi), male Wistar rats were initiated with
N-methyl-N-nitrosourea (MNU) (20mg/kg b.w. i.p.) twice a week for 4 weeks, and then given basal diet containing 5% TPA, 5% TPA plus 4%
Sodium bicarbonate (NaHCO(3)) or 1% TPA for the next 22 weeks. Major regulatory
proteins in G1 cell cycle checkpoint including
p16(INK4a),
cyclin-dependent kinase 4 (Cdk4),
cyclin D(1),
retinoblastoma protein (pRb) were determined during various stages of urinary bladder
carcinogenesis by using immunohistochemistry. In MNU-5% TPA treated group, the incidences of overexpression of Cdk4,
cyclin D(1) and pRb in
papilloma were significantly higher than these in simple
hyperplasia (p=0.023, p<0.001 and 0.001, respectively) and in PN
hyperplasia (p=0.042, 0.012 and 0.002, respectively). The incidence of absent expression of
p16(INK4a) in
papilloma was much higher than that in simple
hyperplasia (p=0.004) and in PN
hyperplasia (p=0.02). Our results clearly reveal that the deregulation of p16(INK4a)-cyclin D(1)/Cdk4-pRb pathway is associated with bladder
carcinogenesis promoted by TPA-
calculi.