Protective actions of vitamin D in UVB induced skin cancer

Abstract

Non-melanoma skin cancers (NMSC) are the most common type of cancer, occurring at a rate of over 1 million per year in the United States. Although their metastatic potential is generally low, they can and do metastasize, especially in the immune compromised host, and their surgical treatment is often quite disfiguring. Ultraviolet radiation (UVR) as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVR is also required for vitamin D synthesis in the skin. Based on our own data and that reported in the literature, we hypothesize that the vitamin D produced in the skin serves to suppress UVR epidermal tumor formation. In this review we will first discuss the evidence supporting the conclusion that the vitamin D receptor (VDR), with or without its ligand 1,25-dihydroxyvitamin D, limits the propensity for cancer formation following UVR. We will then explore three potential mechanisms for this protection: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR).

Fig. 1

Production of vitamin D and its metabolism to 1,25(OH)₂D in the keratinocyte. UVB, via a photochemical reaction, breaks open the B ring of 7-dehydrocholesterol (7-DHC) to produce pre vitamin D₃, which is subsequently converted first to 25OHD by the enzymes CYP27A1 and CYP2R1 and then to 1,25(OH)₂D by CYP27B1. Regulation of CYP27B1 is primarily by cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ(IFN-γ).

Fig. 2

The hedgehog signaling pathway. In the absence of Shh, Ptch 1 suppresses signaling by smoothened (Smo). Binding of Shh to Ptch 1 relieves this inhibition. Activation of Smo leads to the activation and translocation of transcription factors of the Gli family into the nucleus, with subsequent changes in gene expression.

Fig. 3

The wnt signaling pathway. Wnts bind to their frizzled receptors (FZ) and coreceptors LRP in the membrane. This binding can be blocked by dickkopf (Dkk) or soluble frizzled related proteins (sFRP). Activation of FZ by wnt results in phosphorylation of disheveled (Dvl) which induces the disruption of the axin/APC/GSK-3β complex and recruitment of axin to the membrane. When active, this complex phosphorylates β-catenin, leading to its proteosomal degradation. However, following wnt stimulation, β-catenin is no longer degraded and can enter the nucleus, where in combination with members of the LEF/TCF family, it can induce expression of its target genes such as cyclin D1. β-Catenin also binds to the E-cadherin complex in the plasma membrane, a complex stabilized by calcium, where it may play a role in differentiation.