Vitamin D3 receptor ablation sensitizes skin to chemically induced tumorigenesis
Vitamin D3 receptor ablation sensitizes skin to chemically induced tumorigenesis
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DOI：
10.1093/carcin/23.12.2103
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发表时间：
2002-12-01
期刊：
影响因子：
4.7
通讯作者：
Welsh, J
中科院分区：
文献类型：
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作者：
Zinser, GM;Sundberg, JP;Welsh, J
1，25-二羟基维生素D-3（1，25 D（3））是维生素D3的生物活性形式，可与核维生素D3受体（VDR）相互作用，以组织特异性方式调节基因表达。1，25 D（3）是多种细胞类型（包括角质形成细胞）中细胞增殖、分化和凋亡的有效调节剂。在这些研究中，我们评估了VDR无效等位基因纯合子小鼠（VDR-/-小鼠）及其野生型小鼠（VDR+/+小鼠）对口服致癌物7，12-二甲基苯并蒽（DMBA）的敏感性。尽管该方案针对乳腺肿瘤的诱导进行了优化，但85%的VDR-/-小鼠在致癌物暴露60天内发生了持续性皮肤肿瘤。在暴露于DMBA的VDR-/-小鼠中，乳头状瘤出现在身体的所有区域，平均肿瘤负荷为5.3乳头状瘤/小鼠。在给予DMBA的年龄和性别匹配的VDR+/+小鼠中未观察到乳头状瘤或任何其他皮肤病变，并随访6个月。VDR-/-小鼠中发生的大多数（80%）皮肤肿瘤在组织学上被分类为皮脂腺、鳞状或滤泡性乳头状瘤。在暴露于DMBA的VDR-/-小鼠（但不在VDR+/+小鼠）中偶尔观察到其他类型的病变，包括基底细胞癌、血管瘤和黑色素病灶。表皮厚度和BrdU掺入的定量表明，VDR-/-小鼠的皮肤在7周龄时开始表现出过度增殖，DMBA处理加剧了这种过度增殖。未经治疗的老龄VDR-/-小鼠没有表现出肿瘤形成，但确实发展出以增厚的皱纹皮肤、皮样囊肿和长卷曲指甲为特征的进行性皮肤表型。结合先前的报道，1，25 D（3）抑制局部DMBA-TPA方案诱导的乳头状瘤形成，我们观察到VDR-/-小鼠对化学诱导的皮肤癌发生的敏感性增强，这为VDR信号传导的破坏易诱发肿瘤提供了令人信服的证据。
1,25-Dihydroxyvitamin D-3 (1,25D(3)) is the biologically active form of vitamin D3 that interacts with the nuclear vitamin D3 receptor (VDR) to modulate gene expression in a tissue-specific fashion. 1,25D(3) is a potent regulator of cell proliferation, differentiation and apoptosis in a variety of cell types, including keratinocytes. In these studies, we assessed the sensitivity of mice homozygous for a null allele of the VDR (VDR-/- mice) and their wild-type counterparts (VDR+/+ mice) to oral administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA). Although the protocol was optimized for the induction of mammary tumors, 85% of VDR-/- mice developed persistent skin tumors within 60 days of carcinogen exposure. In VDR-/- mice exposed to DMBA, papillomas arose on all areas of the body, with an average tumor burden of 5.3 papillomas/mouse. No papillomas or any other skin lesions were observed in age- and sex-matched VDR+/+ mice dosed with DMBA and followed for 6 months. The majority (80%) of skin tumors that developed in VDR-/- mice were classified histologically as sebaceous, squamous or follicular papillomas. Other types of lesions, including basal cell carcinoma, hemangioma and melanotic foci, were occasionally observed in VDR-/- mice (but not in VDR+/+ mice) exposed to DMBA. Quantification of epidermal thickness and BrdU incorporation indicated that skin from VDR-/- mice exhibited hyperproliferation beginning at 7 weeks of age, which was exacerbated by DMBA treatment. Untreated aging VDR-/- mice did not exhibit tumor formation, but did develop a progressive skin phenotype characterized by thickened wrinkled skin, dermoid cysts and long curly nails. Together with previous reports that 1,25D(3) inhibits papilloma formation induced by topical DMBA-TPA regimens, our observation of enhanced sensitivity of VDR-/- mice to chemically induced skin carcinogenesis offers compelling evidence that disruption of VDR signaling predisposes to neoplasia.