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Review
. 2018 Jan;34(1):13-24.
doi: 10.1111/phpp.12329. Epub 2017 Aug 2.

Mechanisms and prevention of UV-induced melanoma

Ashley Sample  1   2 , Yu-Ying He  1   2
Affiliations
Review

Mechanisms and prevention of UV-induced melanoma

Ashley Sample et al. Photodermatol Photoimmunol Photomed. 2018 Jan.

Abstract

Melanoma is the deadliest form of skin cancer and its incidence is rising, creating a costly and significant clinical problem. Exposure to ultraviolet (UV) radiation, namely UVA (315-400 nm) and UVB (280-315 nm), is a major risk factor for melanoma development. Cumulative UV radiation exposure from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin. A number of factors, including hair color, skin type, genetic background, location, and history of tanning, determine the skin's response to UV radiation. In melanocytes, dysregulation of this UV radiation response can lead to melanoma. Given the complex origins of melanoma, it is difficult to develop curative therapies and universally effective preventative strategies. Here, we describe and discuss the mechanisms of UV-induced skin damage responsible for inducing melanomagenesis, and explore options for therapeutic and preventative interventions.

Keywords: UV; melanoma; prevention.

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Figures

Figure 1
Figure 1. UVB response in melanoma
UVB exposure triggers macrophage and neutrophil infiltration into the skin. Upregulation of CCR2 and ATF2 in melanocytes promotes recruitment of macrophages into the skin, which in turn stimulates production of CCL2, MMP-9, and IFN-γ in macrophages. IFN-γ signaling from macrophages promotes a positive feedback loop between melanocytes and macrophages, in which melanocytes upregulate CCL8, a CCR2 ligand, and promote further recruitment of macrophages. The inflammatory response created by macrophage and neutrophil recruitment promotes angiogenesis, as well as melanoma cell invasion, survival, and metastasis. UVB also independently regulates melanin production and MC1R signaling. Induction of pigmentation genes and subsequent increase in melanin production following UVB increases cell survival and NER, but decreases proliferation and ultimately, melanomagenesis. Signaling through MC1R is induced by UVB and activates DNA damage response. Signaling through αMSH and MC1R promotes phosphorylation of ATM and ATR, upregulates XPC, and promotes XPA recruitment to stimulate NER. αMSH also activates oxidative stress response genes to reduce oxidative stress in melanocytes/melanoma. UVB-induced expression of IL-23 also activates XPC and XPA to induce NER. IL-23 signaling, melanin production, and MC1R signaling can all inhibit melanomagenesis induced by UVB.
Figure 2
Figure 2. UVA response in melanoma
UVA is known to directly induce oxidative stress in melanocytes, but recent work suggests that UVA perpetuates the accumulation of oxidative stress through several mechanisms. UVA induces Sestrin2, a negative regulator of Nrf2 to promote oxidative stress accumulation in melanocytes. Furthermore, UVA suppresses OGG1, impairing repair of oxidative lesions and furthering oxidative stress. Oxidative stress can ultimately lead to the accumulation of “dark CPDs” hours after UVA exposure.
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