Enhanced skin carcinogenesis in transgenic mice with high expression of glutathione peroxidase or both glutathione peroxidase and superoxide dismutase

Yao Ping Lu, You Rong Lou, Patricia Yen, Harold L. Newmark, Oleg I. Mirochnitchenko, Masayori Inouye, Mou Tuan Huang

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Female transgenic mice (C57BL/6 x CBA/J)F1 with a 1-fold increase in expression of glutathione peroxidase (GP) or with a 1-fold increase in the expression of GP and a 3-4-fold increase in the expression of superoxide dismutase (SOD) had an enhanced carcinogenic response to initiation by 7,12- dimethylbenz[a]anthracene (DMBA) followed by promotion with 12-O- tetradecanoylphorbol-13-acetate (TPA). GP- or GP+SOD-transgenic mice that were initialed by a single topical application of 200 nmol of DMBA followed by promotion with 8 nmol of TPA twice weekly for 30 weeks developed an average of 10.9 or 11.0 skin tumors per mouse and a 100% tumor incidence in comparison with the corresponding nontransgenic mice, which had 3.9 tumors per mouse and an 83% tumor incidence. After stopping TPA application, partial skin tumor regression occurred more rapidly in nontransgenic mice than in either type of transgenic mouse. At 10 weeks after termination of TPA treatment, 9-11% of the tumor-bearing transgenic mice and 26% of the tumor- bearing nontransgenic mice had complete regression of their tumors. Histopathological examination of 96 skin papillomas revealed that the area, location, degree of tumor dysplasia, bromodeoxyuridine labeling index, and p53 protein levels were closely intercorrelated. Further analysis indicated that papillomas with the same grade of dysplasia had a higher bromodeoxyuridine labeling index and a greater p53 protein level in GP- or GP+SOD-transgenic mice than those in nontransgenic mice. The data indicated that overexpression of skin antioxidant enzymes GP or GP+SOD, which are enzymes that are believed to protect cells from oxidative damage by scavenging reactive oxygen species, lead to the increased, rather than the decreased, tumorigenesis in a DMBA/TPA two-stage skin carcinogenesis model.

Original languageEnglish (US)
Pages (from-to)1468-1474
Number of pages7
JournalCancer Research
Volume57
Issue number8
StatePublished - 1997

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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