The Role of the Vitamin D Receptor in the Pathogenesis, Prognosis, and Treatment of Cutaneous Melanoma

Abstract

Melanoma is the malignant transformation of melanocytes and represents the most lethal form of skin cancer. While early-stage melanoma localized to the skin can be cured with surgical excision, metastatic melanoma often requires a multi-pronged approach and even then can exhibit treatment resistance. Understanding the molecular mechanisms involved in the pathogenesis of melanoma could lead to novel diagnostic, prognostic, and therapeutic strategies to ultimately decrease morbidity and mortality. One emerging candidate that may have value as both a prognostic marker and in a therapeutic context is the vitamin D receptor (VDR). VDR is a nuclear steroid hormone receptor activated by 1,25 dihydroxy-vitamin D3 [calcitriol, 1,25(OH)₂D3]. While 1,25 dihydroxy-vitamin D3 is typically thought of in relation to calcium metabolism, it also plays an important role in cell proliferation, differentiation, programmed-cell death as well as photoprotection. This review discusses the role of VDR in the crosstalk between keratinocytes and melanocytes during melanomagenesis and summarizes the clinical data regarding VDR polymorphisms, VDR as a prognostic marker, and potential uses of vitamin D and its analogs as an adjuvant treatment for melanoma.

Keywords: heterodimers; melanoma; pathogenesis; polymorphisms; therapy; tumor microenvironment; vitamin D receptor (VDR); vitamin D3 metabolite.

Figure 1

The intracellular action of vitamin D3 (D3)- and lumisterol (L3)-hydroxyderivatives in photoprotection against UVR. Signal transduction includes the activation of nuclear receptors such as vitamin D receptor (VDR), retinoic acid orphan receptor (ROR)α/γ, and aryl hydrocarbon receptor (AhR) and the direct action of D3- and L3-hydroxyderivatives on mitochondrial processes. The nuclear receptors activities are linked with the transcriptional master regulators NRF2 (nuclear factor erythroid-derived 2-like 2), p53 and NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) to coordinate anti-oxidative, DNA repair, anti-inflammatory, and antiproliferative as well as anti-carcinogenesis mechanisms. The figure is reprinted from (45) with a permission from the publisher.

Figure 2

(A) Mechanism of action of canonical and non-canonical vitamin D-hydroxyderivatives. Vitamin D signaling in mononuclear cells downregulates inflammatory genes and suppresses oxidative stress. VDR, vitamin D receptor; RXR, retinoid X receptor; ROR, retinoic acid orphan receptor, ROR, ROR response element; ARE, antioxidant response element; VDRE, vitamin D response element; NRF2, nuclear factor erythroid-derived 2-like 2. (B) Different routes of vitamin D delivery will impact vitamin D activation pattern. The figure is reprinted from (46) with a permission from the publisher.