Carcinogenesis Advance Access published online on March 28, 2003
Carcinogenesis, doi:10.1093/carcin/bgg052
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8503, Japan
* Corresponding author. E-mail: ctohyama{at}nies.go.jp..
Received 22 July 2002
; revised 10 February 2003
; accepted 13 March 2003
To clarify the physiological role(s) of metallothionein (MT) in carcinogenesis, we studied the susceptibility of MT-null mice to chemically-mediated carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced two-stage carcinogenesis model by utilizing MT-null mice. The MT-null mice were subjected to a single topical application of DMBA (50 or 100 µg/mouse) and, 1 week later, to promotion with TPA (10 µg/mouse) twice a week for 20 weeks. At week 21, nearly all of the MT-null mice developed tumors in the skin in contrast to only 10-40% of wild-type mice. No tumor was observed in MT-null or wild-type mice that were administered TPA alone. By using PCR-restriction fragment length polymorphism (PCR-RFLP) and PCR-single-strand conformation polymorphism (PCR-SSCP) methods, we found a transversion of A182 to T of codon 61 of the c-Ha-ras in the papilloma tissue of MT-null mice and wild-type mice but failed to find any mutations in c-Ki-ras and c-N-ras genes. In the two-stage skin carcinogenesis by DMBA/TPA, p53 and p21WAF1/Cip1 expression levels were found to be increased in MT-null mice compared with wild-type mice. As to an earlier change at the promotion stage triggered by TPA application, MT-null mice were found to have both hyperplasia of the epithelium and a marked degree of inflammation in the basal layer, indicating that the induced as well as endogenous MT acted as a protective factor against tumorigenesis. In conclusion, the present study demonstrated that MT has and anti-tumorigenic potential both at initiation and promotion stage of the two stage chemical skin carcinogenesis model.
metallothionein, papilloma, DNA damage, ras, mutation
Metallothionein deficiency enhances skin carcinogenesis induced by 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate in Metallothioenin-null mice
2 Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8503, Japan; Department of Toxicology, School of Public Health, Beijing University, Beijing 100083, China
3 Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8503, Japan; Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
4 Department of Biology, Kyoritsu College of Pharmacy, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512, Japan
5 Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8503, Japan; Department of Hygienics, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
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