Department of Dermatology, Saarland University, Campus Homburg, Homburg, Germany.
José Carreras Center and Internal Medicine I, Saarland University, Campus Homburg, Homburg, Germany.
Anticancer Res. 2022 Oct;42(10):5049-5067. doi: 10.21873/anticanres.16014. Epub 2022 Oct 3.
BACKGROUND/AIM: Vitamin D receptor (VDR), activated upon binding of 1,25(OH)D, was described as a tumor suppressor in the skin. New biological functions of non-classical vitamin D derivatives were recently identified, that are mediated via binding to alternate receptors, including the aryl hydrocarbon receptor (AHR) and that indicate functional interaction between AHR and VDR signaling in various human tissues. We aimed to gain further insights into the cross-talk of VDR and AHR signaling in skin photo-carcinogenesis.
Using real-time quantitative PCR, we analyzed in vitro effects of the complete carcinogen UVB and of 1,25(OH)D on the expression of members of the AHR and VDR pathways in human keratinocytes revealing characteristics of different stages of skin photo-carcinogenesis.
In precancerous HaCaT keratinocytes, induction of a target gene of AHR-mediated transcription (CYP1A1) was markedly stronger after treatment with UVB, as compared to treatment with 1,25(OH)2D3. In contrast, in SCL-1 cells (that reveal the complete phenotype of malignant transformation), expression of CYP1A1 was higher after treatment with 1,25(OH)D as compared to treatment with UVB. The classical VDR target CYP24A1 was up-regulated by 1,25(OH)D, but not by UVB, in both cell lines. However, the combined treatment with UVB strongly enhanced the 1,25(OH)D-mediated up-regulation of CYP24A1 exclusively in SCL-1, but not in HaCaT cells.
There is a differential regulation of VDR and AHR target genes by UVB and 1,25(OH)D in HaCaT and SCL-1 cells, that points to a complex and highly orchestrated network of vitamin D derivatives (and other photoproducts) and its relevance for photo-carcinogenesis.
背景/目的：维生素 D 受体 (VDR) 在与 1,25(OH)D 结合后被描述为皮肤中的肿瘤抑制因子。最近发现了非经典维生素 D 衍生物的新生物学功能，这些功能通过与替代受体结合介导，包括芳香烃受体 (AHR)，并表明在各种人体组织中 AHR 和 VDR 信号之间存在功能相互作用。我们旨在进一步深入了解 VDR 和 AHR 信号在皮肤光致癌中的相互作用。
使用实时定量 PCR，我们分析了完全致癌的 UVB 和 1,25(OH)D 对体外人角质形成细胞中 AHR 和 VDR 途径成员表达的影响，揭示了皮肤光致癌不同阶段的特征。
在癌前 HaCaT 角质形成细胞中，与用 1,25(OH)2D3 处理相比，用 UVB 处理后 AHR 介导的转录的靶基因 (CYP1A1) 的诱导明显更强。相比之下，在 SCL-1 细胞（显示出恶性转化的完整表型）中，用 1,25(OH)D 处理后 CYP1A1 的表达高于用 UVB 处理后。经典的 VDR 靶标 CYP24A1 被 1,25(OH)D 上调，但在两种细胞系中均不受 UVB 上调。然而，UVB 的联合处理仅在 SCL-1 细胞中而非 HaCaT 细胞中强烈增强了 1,25(OH)D 介导的 CYP24A1 上调。
在 HaCaT 和 SCL-1 细胞中，UVB 和 1,25(OH)D 对 VDR 和 AHR 靶基因的调节存在差异，这表明维生素 D 衍生物（和其他光产物）的复杂和高度协调的网络及其与光致癌的相关性。
