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Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

Departments of ¹ Otolaryngology, ² Dermatology, and ³ Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon; and ⁴ Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

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)- 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-ß1 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-ß1–responsive genes, which are required for tumor promotion, and through mediating TGF-ß1–induced macrophage infiltration.

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