Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis.
It has been shown that Smad3 exerts both tumor-suppressive and -promoting roles. To evaluate the role of Smad3 in skin carcinogenesis in vivo, we applied a chemical skin carcinogenesis protocol to Smad3 knockout mice (Smad3(-/-) and Smad3(+/-)) and wild-type littermates (Smad3(+/+)). Smad3(-/-) mice exhibited reduced papilloma formation in comparison with Smad3(+/+) mice and did not develop any squamous cell carcinomas. Further analysis revealed that Smad3 knockout mice were resistant to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal hyperproliferation. Concurrently, increased apoptosis was observed in TPA-treated Smad3(-/-) skin and papillomas when compared with those of wild-type mice. Expression levels of activator protein-1 family members (c-jun, junB, junD, and c-fos) and transforming growth factor (TGF)-alpha were significantly lower in TPA-treated Smad3(-/-) skin, cultured keratinocytes, and papillomas, as compared with Smad3(+/+) controls. Smad3(-/-) papillomas also exhibited reduced leukocyte infiltration, particularly a reduction of tumor-associated macrophage infiltration, in comparison with Smad3(+/+) papillomas. All of these molecular and cellular alterations also occurred to a lesser extent in Smad3(+/-) mice as compared with Smad3(+/+) mice, suggesting a Smad3 gene dosage effect. Given that TGF-beta1 is a well-documented TPA-responsive gene and also has a potent chemotactic effect on macrophages, our study suggests that Smad3 may be required for TPA-mediated tumor promotion through inducing TGF-beta1-responsive genes, which are required for tumor promotion, and through mediating TGF-beta1-induced macrophage infiltration.
Li
Allen G
AG
Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon, USA.
Lu
Shi-Long
SL
Zhang
Ming-Xiang
MX
Deng
Chuxia
C
Wang
Xiao-Jing
XJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D004198:Disease Susceptibility; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000517:prevention & control; D015603:Keratinocytes / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D051900:Smad3 Protein; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D015534:Trans-Activators / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000032:analysis
D004268:DNA-Binding Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016211:Transforming Growth Factor alpha; D013755:Tetradecanoylphorbol Acetate