Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis
Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis
复制标题
DOI：
10.1038/jid.2008.131
复制
发表时间：
2008-10-01
影响因子：
6.5
通讯作者：
MacDonald, Paul N.
中科院分区：
文献类型：
--
作者：
Ellison, Tara I.;Smith, Molly K.;MacDonald, Paul N.
1，25-二羟基维生素D3（1，25（OH）（2）D-3）是维生素D受体（VDR）的生物活性配体。VDR-/-小鼠具有导致脱发的毛囊循环缺陷。然而，缺乏25-羟基维生素D3 1a-羟化酶（CYP 27 B1（-/-））且没有循环1，25（OH）2D 3的小鼠具有正常的卵泡功能。这些小鼠模型表明VDR在调节毛囊周期中独立于1，25（OH）2D 3发挥作用。在这里，我们发现VDR-/-小鼠迅速发展化学诱导的皮肤肿瘤，而CYP 27 B1（-/-）和野生型小鼠没有，表明VDR，而不是1，25（OH）2D 3配体，是防止皮肤肿瘤发生所必需的。由于大多数人类皮肤癌是由暴露于紫外线引起的，因此还评估了VDR-/-小鼠对该致癌物的易感性。VDR-/-小鼠比VDR-/-小鼠更快地产生紫外线诱导的肿瘤，并且外显率更高。在VDR-/-和VDR-/-小鼠的UV处理的角质形成细胞中，p53蛋白水平以相似的速率上调。然而，与野生型表皮相比，VDR-/-表皮的胸腺嘧啶二聚体修复率和UV诱导的细胞凋亡率显著降低。UV诱导的表皮增厚在VDR-/-皮肤中也减弱，表明VDR在修复和去除严重受损的角质形成细胞以及皮肤适应慢性UV暴露中起关键作用。
1,25-Dihydroxyvitamin D3 (1,25(OH)(2)D-3) is the biologically active ligand for the vitamin D receptor (VDR). VDR-/- mice have a hair follicle-cycling defect resulting in alopecia. However, mice lacking 25-hydroxyvitamin D3 1a-hydroxylase (CYP27B1(-/-)), and having no circulating 1,25(OH) 2D3, have normal follicular function. These mouse models indicate that VDR functions independently of 1,25(OH) 2D3 in regulating hair-follicle cycling. Here, we show that VDR-/- mice rapidly develop chemically induced skin tumors, whereas CYP27B1(-/-) and wild-type mice do not, indicating that VDR, and not the 1,25(OH) 2D3 ligand, is essential for protection against skin tumorigenesis. Because the majority of human skin cancer results from exposure to UV, the susceptibility of VDR-/- mice to this carcinogen was also evaluated. VDR-/- mice developed UV-induced tumors more rapidly and with greater penetrance than did VDR-/- mice. p53 protein levels were upregulated at similar rates in UV-treated keratinocytes of VDR-/- and VDR-/- mice. However, rates of thymine-dimer repair and UV-induced apoptosis were significantly lower in VDR-/- epidermis compared with the wild type epidermis. UV-induced epidermal thickening was also attenuated in VDR-/- skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes and adaptation of the skin to chronic UV exposure.