The loss of Tm7sf gene accelerates skin papilloma formation in mice

The 3b-hydroxysterol D14-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 Tm7sf21/1 and Tm7sf2-/- mice. TPA increased<br>skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf21/1 mouse, confirming that<br>the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major<br>players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this<br>response was lost in Tm7sf2-/- mice. The expression of markers of epidermal differentiation concomitant<br>with farnesoid-X-receptor and p38 MAPK activation were also disrupted in Tm7sf2-/- mice. We then<br>subjected Tm7sf21/1 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.

由Tm7sf2基因编码的3β-羟基甾醇D14还原酶（3b-hydroxysterol D14-reductase）是一种参与胆固醇生物合成的酶。胆固醇及其衍生物可维持表皮屏障完整性，并抵御环境应激损伤。为明确该基因在皮肤胆固醇稳态中的作用，我们向Tm7sf21/1与Tm7sf2-/-小鼠的皮肤涂抹了12-O-十四烷酰佛波醇-13-乙酸酯（12-o-tetradecanoylphorbol-13-acetate，TPA）。实验结果显示，TPA仅能在Tm7sf21/1小鼠中通过诱导胆固醇从头合成与摄取提升皮肤胆固醇水平，证实该基因可在应激条件下维持皮肤胆固醇稳态。硫酸胆固醇是调控皮肤通透性的关键物质之一，野生型小鼠皮肤经TPA处理后其含量翻倍，但该响应在Tm7sf2-/-小鼠中完全消失。与此同时，表皮分化标志物的表达以及法尼醇X受体（farnesoid-X-receptor）与p38丝裂原活化蛋白激酶（p38 MAPK）的激活在Tm7sf2-/-小鼠中均受到显著干扰。随后，我们对Tm7sf21/1与Tm7sf2-/-小鼠实施经典的两步皮肤致癌方案，结果发现Tm7sf2基因缺失会升高皮肤乳头状瘤的发生率与多发数量。值得注意的是，该敲除基因型小鼠的nur77基因（nur77）表达量显著降低，而nur77基因与肿瘤转化抗性密切相关。综上，Tm7sf2基因缺失会通过降低硫酸胆固醇水平，干扰参与表皮分化的蛋白质的表达。