Expression of dominant negative c-jun inhibits ultraviolet B-induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model.
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.
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D016758:Genes, jun / Q000235:genetics*; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D019938:Cyclin D1