Journal Article

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

Junko S. Suzuki, Noriko Nishimura, Baoxu Zhang, Yoko Nakatsuru, Shizuko Kobayashi, Masahiko Satoh and Chiharu Tohyama

in Carcinogenesis

Volume 24, issue 6, pages 1123-1132
Published in print June 2003 | ISSN: 0143-3334
Published online June 2003 | e-ISSN: 1460-2180 | DOI:
Metallothionein deficiency enhances skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate in metallothionein-null mice

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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.

Keywords: BrdU, 5′-bromo-2′-deoxyuridine; DMBA, 7,12-dimethylbenz[a]anthracene; MT, metallothionein; 8-OH-dG, 8-hydroxy-2′-deoxyguanosine; PCR–RFLP, PCR–restriction fragment length polymorphism; PCR–SSCP, PCR–single strand conformation polymorphism; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Journal Article.  7388 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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