Figure 5.

c-Fos expression accelerates DMBA-induced papilloma and SCC development. (A) Scheme of the experimental design: Six-week-old (6w) mice were given a topical single dose of DMBA (0.5% [w/v] in acetone), and Dox was supplied 1 wk later (1w) in the water at a concentration of 0.25 g/L. (B) Representative picture of control (littermate) and c-Fos^Ep-tetON (n = 10). (C) Quantification of the papilloma number after 8 wk of inducible c-fos expression. (D) Tumor size in c-Fos^Ep-tetON female and male mice after DMBA and 8 and 11 wk of inducible c-fos expression. Mean ± SEM. (E) mRNA expression analyses of c-fos, mmp10, and s100a7a15 in control back skin and c-Fos^Ep-tetON SCCs. (F) Scheme of the experimental design: Six-week-old mice were given a topical single dose of DMBA (0.5% [w/v]), and Dox was supplied 1 wk later (7w) in the food pellets. Sulindac was supplied in the drinking water at a concentration of 180 mg/L. (G, top panels) Representative pictures of DMBA-treated c-Fos^Ep-tetON mice ± sulindac treatment after 7 wk of inducible c-fos expression. (Bottom)Immunohistochemical analyses depicting H&E and cleaved caspase 3 (cl.caspase 3) immunostaining of the back skin of DMBA-treated c-Fos^Ep-tetON mice ± sulindac treatment after 7 wk of inducible c-fos expression. (H) Lesion number quantified when the mice were sacrificed, comparing controls and c-Fos^Ep-tetON mice treated with DMBA ± sulindac. (I) Lesion size quantified when the mice were sacrificed, comparing controls and c-Fos^Ep-tetON mice treated with DMBA ± sulindac. (J) Schematic representation of changes in the epidermis upon induction of c-Fos, leading to increased MMP10 and S100a7a15 and, subsequently, the recruitment of CD4 T cells. As a consequence, paracrine cytokine signaling (IL-22) promotes keratinocyte proliferation and survival, leading to epidermal hyperplasia and, when combined with DMBA, SCC development.