The loss of Tm7sf gene accelerates skin papilloma formation in mice

The 3β-hydroxysterol Δ14-reductase, encoded by the Tm7sf2 gene, is an enzyme involved in cholesterol biosynthesis. Cholesterol and its derivatives control epidermal barrier integrity and are protective against environmental insults. To determine the role of the gene in skin cholesterol homeostasis, we applied 12-o-tetradecanoylphorbol-13-acetate (TPA) to the skin of Tm7sf2(+/+) and Tm7sf2(-/-) mice. TPA increased skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf2(+/+) mouse, confirming that the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this response was lost in Tm7sf2(-/-) mice. The expression of markers of epidermal differentiation concomitant with farnesoid-X-receptor and p38 MAPK activation were also disrupted in Tm7sf2(-/-) mice. We then subjected Tm7sf2(+/+) and Tm7sf2(-/-) mice to a classical two-stage skin carcinogenesis protocol. We found that the loss of Tm7sf2 increased incidence and multiplicity of skin papillomas. Interestingly, the null genotype showed reduced expression of nur77, a gene associated with resistance to neoplastic transformation. In conclusion, the loss of Tm7sf2 alters the expression of proteins involved in epidermal differentiation by reducing the levels of cholesterol sulfate.