Carcinogenesis, Vol. 21, No. 1, 117-121,
January 2000
© 2000 Oxford University Press
Carcinogenesis |
Aberrant expression of p27Kip1 is associated with malignant transformation of the rat urinary bladder epithelium
1 First Department of Pathology and
2 Second Department of Biochemistry, Nagoya City University, Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601,
3 Nagoya-shi Kohseiin Geriatric Hospital, 2-1501 Sekobou, Meito-ku, Nagoya 465-0055, Japan
Alteration in cell cycle regulators is considered to play an important role in carcinogenesis. In order to cast light on changes in reversible hyperplastic and irreversible tumorigenic lesions in the rat urinary bladder, expression of p27Kip1, cyclin D1 and cyclin E proteins was sequentially compared. In the first study, 3% uracil was fed for 4 weeks to cause urinary calculi and consequent hyperplasia and papillomatosis, both regressing after withdrawal of the insult. Compared with normal bladder epithelium, in papillomatosis at week 4, the BrdU index and immunohistochemical positivities for cyclin D1 and cyclin E were significantly elevated, whereas values for p27Kip1 tended to be reduced. One week after withdrawal of uracil, the BrdU index and positivities for cyclin D1 and cyclin E were decreased to below the control levels, while positivity for p27Kip1 was dramatically increased, with a strong staining intensity. In a second study, rats were initiated with a bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine for 4 weeks, then fed 3% uracil for 8 weeks. During this latter period, expression of cyclin D1, cyclin E and p27Kip1 in hyperplastic urothelium were comparable with those in the first study. One week after withdrawal of uracil, most urothelial lesions regressed, showing high p27Kip1 and low cyclin D1 and cyclin E staining. Two weeks after uracil withdrawal, transitional cell carcinomas, with a low p27Kip1 and high cyclin D1 and cyclin E staining pattern, could be easily distinguished from surrounding regressing epithelium. These data indicate that during regression of papillomatosis after cessation of a proliferative stimulus, expression of p27Kip1is elevated, accompanied by a lowering of cyclin D1 and cyclin E. In irreversible tumorous bladder lesions, on the other hand, persistent low expression of p27Kip1 and elevated cyclin D1 and cyclin E are characteristic.
Abbreviations: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; BrdU, bromodeoxyuridine.
4 To whom correspondence should be addressed at: First Department of Pathology, Nagoya City University, Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Email: kogawa{at}med.nagoya-cu.ac.jp
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