Altered expression of transforming growth factor‐β1 mrna and protein in mouse skin carcinogenesis

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Abstract
Transforming growth factor (TGF)-β1, whose gene is located on mouse chromosome 7, has been proposed to be involved in skin carcinogenesis. In the study presented here, we demonstrated that single topical treatments with different types of tumor promoters, i.e., the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 μg); the non–protein kinase C activators anthralin (22.6 μg), benzoyl peroxide (20 mg), and cumene hydroperoxide (1.2 mg); the first-stage tumor promoters 4-O-methyl-TPA (500 μg) and A23187 (166 μg); and the second-stage tumor promoter mezerein (2 μg) produced transient induction of TGF-β1 mRNA in SSIN (inbred SENCAR) mouse skin. The time of maximum induction varied from 3 to 12 h; the relative extent of induction was ranked as cumene hydroperoxide > benzoyl peroxide > anthralin > TPA > 4-O-methyl-TPA > mezerein > A23187. These findings suggested that TGF-β1 mRNA induction is a common response of skin to several types of complete and stage-specific promoters; however, the extent of induction did not correlate with the reported hyperplastic activity of single applications of these promoters. We also demonstrated that TGF-β1 mRNA expression in papillomas of SENCAR mice generally correlated with expression levels of cyclin D1, another gene on chromosome 7, and with stage of tumor progression. TGF-β1 mRNA expression was constitutively elevated in most squamous cell carcinomas from either initiation-promotion or complete carcinogenesis protocols. Cell lines established from carcinomas also overexpressed TGF-β1 mRNA. Immunohistochemical staining of tissue sections of normal and TPA-treated skin revealed the presence of extracellular TGF-β1 protein in the dermis and intracellular TGF-β1 protein in the epidermis, especially in the suprabasal layers. The staining patterns of papillomas varied, with 62 ± 13% of the tissue showing strong intracellular staining but only 25 ± 8% of the connective tissue staining for extracellular TGF-β1. Variable staining patterns were also found in carcinomas; some areas stained heavily for both the intracellular and extracellular forms of TGF-β1. Overall, 28 ± 6% of the tissue of the 12 analyzed carcinomas stained for the intracellular form and 18 ± 5% for the extracellular from of TGF-β1.