Expression of dominant negative c-jun inhibits ultraviolet B-induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model

• Published in: Molecular cancer research 2003-09, Vol.1 (11), p.848-854
• Main Authors: COOPER, Simon J, MACGOWAN, Jacalyn, RANGER-MOORE, James, YOUNG, Matthew R, COLBURN, Nancy H, BOWDEN, G. Tim
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Biological and medical sciences; Biotechnology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell physiology; Cyclin D1 - metabolism; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Gene therapy; Genes, jun - genetics; Health. Pharmaceutical industry; Hyperplasia - genetics; Hyperplasia - metabolism; Hyperplasia - pathology; Industrial applications and implications. Economical aspects; Mice; Mice, Inbred Strains; Mice, Transgenic; Molecular and cellular biology; Neoplasms, Radiation-Induced - genetics; Neoplasms, Radiation-Induced - pathology; Peptide Fragments - genetics; Peptide Fragments - metabolism; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Time Factors; Transcription Factor AP-1 - metabolism; Transgenes - genetics; Ultraviolet Rays - adverse effects
• ISSN: 1541-7786; 1557-3125

UVB radiation is a complete carcinogen able to initiate, promote, and progress keratinocyte cells toward carcinogenesis. Exposure to UVB leads to the propagation of a number of signal transduction pathways resulting in increased DNA binding of transcription factors, including activator protein-1 (AP-1), and subsequent gene expression. To test the hypothesis that AP-1 activation plays a role in the promotion of UVB-induced skin tumors, a dominant negative c-jun (TAM67) mutant transgene was expressed in the epidermis of SKH-1 hairless mice and bred with mice expressing an AP-1 luciferase reporter gene. Single UVB exposure experiments showed a significant decrease in AP-1 activity, as measured by luciferase levels, in mice expressing TAM67 72 h postexposure. Transgenic and nontransgenic littermates were placed into a chronic UVB exposure experiment, three exposures per week for 25 weeks. Expression of TAM67 reduced the number of tumors per mouse by 58% and tumor sizes were 79% smaller than the tumors present in the nontransgenic study group. These tumors were histologically identified as squamous cell carcinomas. TAM67 had no effect on UVB-induced hyperplasia because comparable epidermal thickening was observed in both study groups over a 5-day period post-UVB exposure. Immunohistochemical analysis showed a reduction in the number of cyclin D(1)-expressing cells in squamous cell carcinoma samples removed from the TAM67 study group. These data show that TAM67 can inhibit UVB-induced squamous cell carcinoma formation, suggesting that AP-1 is a good candidate target for the development of new chemoprevention strategies to prevent sunlight-induced skin cancers.