title: Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Allen G
authors.initials: AG
authors.lastname: Li
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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