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Keratin Gene Expression in Mouse Skin Tumors and in Mouse Skin Treated with 12-O-Tetradecanoylphorbol-13-acetate

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, Maryland 20205

Alternations in the pattern of epidermal differentiation and proliferation occur during mouse skin carcinogenesis. We have used cDNA clones corresponding to the major keratin subunits synthesized in differentiating epidermal cells (M_r 67,000 and 59,000) and in proliferating epidermal cells (M_r 60,000, 55,000 and 50,000) to study changes in keratin gene transcript levels in mouse epidermis exposed to tumor promoters. The same probes were used to characterize the keratin expression patterns in benign and malignant skin tumors. A single topical treatment with 12-O-tetradecanoylphorbol-13-acetate caused a rapid initial decrease in the epidermal transcript levels corresponding to the M_r 67,000 and 59,000 keratin subunits. By 48 h the transcript level for the M_r 67,000 keratin subunit was restored to control values, whereas the transcript levels for the M_r 59,000 subunit returned to control at a slower rate. In contrast, the transcript level for the M_r 55,000 subunit was increased substantially 12–48 h after treatment, the M_r 50,000 subunit transcript increased to a lesser extent, and the M_r 60,000 subunit message was transiently decreased at 12 h but returned to the level of solvent-treated skin by 24 h. Single exposure to the incomplete tumor promoters 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, the ionophore A23187, and mezerein induced changes in keratin gene transcripts similar to those of 12-O-tetradecanoylphorbol-13-acetate. The antipromoter fluocinolone acetonide, administered with 12-O-tetradecanoylphorbol-13-acetate, partially inhibited the decrease in the M_r 59,000 and 67,000 transcripts and completely inhibited the increase in the M_r 55,000 transcript. In skin papillomas produced by initiation and promotion, keratin gene expression was similar to normal skin, with the exception of a two-fold increase in the transcript levels for the M_r 55,000 keratin subunit. However, in carcinomas, the transcript levels for the M_r 67,000 and 59,000 subunits were only 1–3% of those observed in untreated mouse epidermis. In concert with other data, the rapid and selective loss of transcripts for differentiation-related keratins after exposure to both complete and incomplete tumor promoters is most consistent with an accelerated rate of maturation in differentiating keratinocytes, resulting in the rapid production of transcript-depleted fully mature squames. The enhanced level of M_r 55,000 transcripts suggests a concomitant increase in the number of all cells or a subset of cells in the proliferative compartment. Benign tumors, characterized by an increased cellular proliferation rate, may also be enriched in cells transcribing the M_r 55,000 keratin gene, but the differentiating component of papillomas expresses a normal differentiation program with regard to keratins. In carcinomas the cells are blocked in expression of transcripts for keratin subunits associated with differentiation.

¹ Recipient of fellowships from The Swedish Work Environment Health Fund and O. E. and Edla Johanssons Vetenshapliga stiftelse. Present address: Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital F69, S-14186 Huddinge, Sweden.

² To whom requests for reprints should be addressed, at Building 37, Room 3B08, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute; NIH, Bethesda, MD 20205.

Received 5/14/85. Revised 8/ 6/85. Accepted 8/ 9/85.

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