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Carcinogenesis Advance Access originally published online on March 28, 2003
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Carcinogenesis, Vol. 24, No. 6, 1123-1132, June 2003
© 2003 Oxford University Press

CARCINOGENESIS

Metallothionein deficiency enhances skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate in metallothionein-null mice

Junko S. Suzuki1, Noriko Nishimura1, Baoxu Zhang1,2, Yoko Nakatsuru1,3, Shizuko Kobayashi4, Masahiko Satoh1,5 and Chiharu Tohyama1,6

1 Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan
2 Department of Toxicology, School of Public Health, Beijing University, Beijing 100083, China
3 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
4 Department of Biology, Kyoritsu College of Pharmacy, Tokyo 105-8512, Japan
5 Department of Hygienics, Gifu Pharmaceutical University, Gifu 502-8585, Japan

6 To whom correspondence should be addressed Email: ctohyama{at}nies.go.jp

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-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage carcinogenesis model. 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 tumors were observed in MT-null or wild-type mice that were administered TPA alone. By using the PCR–restriction fragment length polymorphism and PCR–single strand conformation polymorphism methods, we found a transversion of A182 to T in codon 61 of c-Ha-ras in the papilloma tissue of MT-null mice and wild-type mice but failed to find any mutations in the c-Ki-ras and c-N-ras genes. In two-stage skin carcinogenesis induction 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 has demonstrated that MT has antitumorigenic potential in both the initiation and promotion stages of the two-stage chemical skin carcinogenesis model.


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