Journal Article

Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with <i>N</i>-butyl-<i>N</i>-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate

Katsumi Takaba, Koji Saeki, Kazuo Suzuki, Hideki Wanibuchi and Shoji Fukushima

in Carcinogenesis

Volume 21, issue 4, pages 691-700
Published in print April 2000 | ISSN: 0143-3334
Published online April 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.4.691
Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate

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Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1–6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4–6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G1 cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.

Keywords: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; BrdU, 5-bromo-2′-deoxyuridine; FCM, flow cytometry; LI, labeling index; MT, metallothionein; Na-AsA, sodium l-ascorbate; PN, papillary or nodular; SEM, scanning electron microscope; TdT, terminal deoxynucleotidyl transferase; TEM, transmission electron microscope; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling.

Journal Article.  7068 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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