Immunohistochemical analysis for cell regulatory proteins in bladder carcinogenesis induced by N-methyl-N-nitrosourea-terephthalic acid

Yuan Shi; Lunbiao Cui; Guidong Dai; Jianfeng Chen; Ling Song; Xinru Wang

doi:10.1016/j.etap.2006.03.002

Immunohistochemical analysis for cell regulatory proteins in bladder carcinogenesis induced by N-methyl-N-nitrosourea-terephthalic acid

Environ Toxicol Pharmacol. 2006 Sep;22(2):172-8. doi: 10.1016/j.etap.2006.03.002. Epub 2006 Mar 16.

Authors

Yuan Shi¹, Lunbiao Cui, Guidong Dai, Jianfeng Chen, Ling Song, Xinru Wang

Affiliation

¹ Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.

PMID: 21783706
DOI: 10.1016/j.etap.2006.03.002

Abstract

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.