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• W2039854661 abstract "Future OncologyVol. 6, No. 10 EditorialFree AccessUltraviolet A light: potential underlying causes of melanomaMoon-shong TangMoon-shong TangDepartment of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd, Tuxedo Park, NY 10987, USA. Search for more papers by this authorEmail the corresponding author at moon-shong.tang@nyumc.orgPublished Online:9 Nov 2010https://doi.org/10.2217/fon.10.129AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: DNA damageDNA repairmelanomaoxidativeultravioletSeveral studies examining which portion of solar ultraviolet (UV) light is responsible for melanoma induction have recently been published [1–3]. Using highly pigmented (75%) Xiphophorus hybrid fish and neonatal mouse models, the results from these studies strongly suggest that UVB (290–320 nm), rather than UVA (320–400 nm), is responsible for inducing melanoma. However, results from epidemiological studies [4], including studies on tanning bed users [5], clearly show that UVA exposure significantly increases the probability of developing melanoma. Although these conclusions are diametrically different in terms of the role of UVA in melanoma, both sets are probably correct in their proper context.Melanoma is a deadly disease, and we are exposed to sunlight almost constantly, out of necessity as well as by choice. Understanding the risks of the different portions of sunlight in melanoma induction will allow individuals to have a balanced view of the pros and cons of sunlight exposure, to make intelligent choices on the proper amount of sunlight exposure and to take the necessary measures to reduce the risk of developing melanoma. In this article, I will attempt to elucidate the effects of UVA irradiation, from biochemistry to biology, in a basic way.First, let us understand the sunlight that reaches the surface of the earth. Thanks to our atmosphere, in particular the ozone layer, most of the harmful UV light is absorbed or reflected back into space and thereby prevented from reaching the surface of the Earth. Of the UV light that does reach the Earth’s surface, 95% is UVA and 5% is UVB [6]. While visible sunlight can penetrate deeply to the dermis and subcutaneous layers of human skin, UVA and UVB can penetrate through the epidermis to the dermis and reach melanocytes, which are embedded at the junction of the epidermis and dermis [6]. Melanocytes are the cells that produce melanin to shield human skin from sunlight and are also the cells that can develop into melanoma.Sunlight causes pleiotropic effects on the human body. Visible sunlight is beneficial and necessary, and UV light has beneficial effects, such as triggering vitamin D synthesis [7]. However, sunlight, particularly UV light, also has many negative effects. UV light causes changes in our genetic material, namely in DNA. UV light induces cyclobutane pyrimidine dimer and pyrimidine<6–4>pyrimidone formation; these two photoproducts can block DNA replication, transcription and affect protein–DNA interactions. If not repaired, they can cause cell death – this is how sunburns start [8]. If these photoproducts are improperly repaired or escape repair processes then they can cause mutations – this is how most skin cancer occur [9]. UV light can also cause damage in cellular RNA and proteins. However, because each cell has multiple copies of these cellular components but only one to two copies of genetic materials, the major damaging effect of UV light resides in the production of these two photoproducts. Generation of these photoproducts is wavelength-dependent and UVB is 1000-fold more efficient than UVA in their production [10]. Sunlight has another important effect, which is the induction of free radicals, including reactive oxygen species (ROS). Excessive ROS can cause DNA damage and lipid peroxidation (LPO). This effect is only notable in melanocytes because melanin can greatly augment this process [11]. In contrast to photoproduct generation, UVA induces much more ROS than does UVB in melanocytes (more than 1000-fold) [11,12].Similarly to UV photoproducts, unrepaired oxidative DNA damage can block DNA replication, transcription and protein–DNA interactions, as well as cause mutations. LPO can trigger further LPO generation and the byproducts of LPO have many adverse effects, including damaging DNA and proteins. The level of LPO byproducts in oxidatively stressed cells frequently reaches 0.1 mM to several mM ranges [13]. My group and others have shown that these byproducts can damage DNA as well as reduce the capacity to repair DNA damage [14,15]. It is abundantly clear from many basic studies that both UVA and UVB irradiation can be harmful to melanocytes and cause mutations in these cells [1–6,12]. The effect of UVB is through photoproduct production in the genome, while that of UVA is through production of free radicals, particularly ROS, which can be augmented greatly in the presence of melanin. It should be noted that in the process of synthesizing melanin from tyrosine precursors, a significant amount of ROS can also be generated and, as a result of natural biochemistry, the production of pheomelanin (the major pigment form in white and light skin) generates more ROS than the production of eumelanin (the major form of pigment in dark skin) [16].More ROS are generated in melanocytes than in other types of skin cells such as keratinocytes, despite the fact that melanin can also scavenge ROS. Melanocytes are constantly under oxidative stress because of melanogensis; we label it ‘melanogensis stress’. We have recently found that melanocytes have a significantly lower repair capacity for both oxidative DNA damage and bulky photoproducts. This inherent deficiency in DNA damage repair makes melanocytes more vulnerable to mutagenesis and tumorigenesis [12]. This may explain why melanocytes in body regions that are never exposed to sunlight can still form mucosal melanomas. DNA damage in these melanocytes could originate from oxidative stress and other metabolites that interact with DNA.Our experimental results show that UVA is harmful to human melanocytes by inducing oxidative DNA damage and that human melanocytes are defective in the repair of DNA damage [12]. Furthermore, DNA damage induces more mutations in human melanocytes than in skin fibroblasts [12]. These results raise two questions: ▪ Is there any evidence that UVA exposure enhances human melanoma incidence?▪ Why are animal models so resistant to UVA-induced melanomagenesis?To answer the first question, there are ample studies indicating that UVA can cause melanoma in humans, but the link may not be immediately apparent without additional analysis [4,17]. First, let us compare the incidences of melanoma and nonmelanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) in countries at different latitudes. The sunlight at different latitudes has not only different intensities but also different UVA:UVB ratios; in northern Scandinavian areas (Norway and Denmark) the UVA:UVB ratio is much higher than in areas closer to the equator, such as in Australia [4,17]. Epidemiologic studies have found that the incidence of nonmelanoma skin cancers and the incidence of melanoma correlate with the UVB:UVA ratio. The nonmelanoma and melanoma incidences in Australia are 555 and 19 per 100,000 population, respectively, while in Scandinavia they are 45 and 11 [4,17]. These results strongly suggest that the high UVA:UVB ratio in Scandinavia plays a role in the disproportionately high melanoma incidence. Correspondingly, the UVB:UVA ratio plays an important role in nonmelanoma skin cancer incidence in Australia. People in Australia are exposed to much more UVB and modestly more UVA than people in Scandinavia, explaining why Australians are much more prone to developing nonmelanoma skin cancer and modestly more prone to developing melanoma than people in Scandinavia. In addition, epidemiologic studies have found that individuals who regularly use a tanning bed (99% of tanning bed light is UVA [18]) have a 74% greater chance of developing melanoma [5]. Simply put, UVA is important in melanomagenesis while UVB is important for nonmelanoma skin cancer.One piece of evidence that is even more insidious is the following: it is well established that melanin protects against the harmful effects of sunlight. However, the ratio of nonmelanoma skin cancer incidence in white-skinned individuals to that in people of African descent in the USA is far greater than that found in melanoma [19]. These results indicate that while melanin may shield melanocytes and skin cells from the ill effects of both UVA and UVB; it may interact with UVA to produce secondary effects that offset its shielding effect on melanomagenesis. UVA and melanin are thus key factors in why, compared with white people, the melanoma incidence in African–Americans is not as low as nonmelanoma skin cancer.Individually, none of these results can unequivocally lead to the conclusion that UVA is the primary culprit for human melanomagenesis. However, when examined collectively, it becomes evident that UVA is the primary culprit [4,5,12,17].Now let us examine UV-induced melanomagenesis in animal models. The only successful examples of UVB-induced melanomagenesis models have been in highly pigmented Xiphophorus hybrids and in neonatal transgenic mice (≤4 days old); successful models of UVA-induced melanomagenesis have only been in Xiphophorus hybrids [20]. Melanocytes in these models have three things in common: they are less differentiated, highly proliferative and contain high levels of melanins. It has been proposed that these melanocytes are ‘primed’ and UV exposure-induced DNA damage can trigger the progression of melanomagenesis; by contrast, highly differentiated melanocytes are resistant to UV-induced melanomagenesis. UV irradiation most likely triggers apoptosis in these differentiated, matured melanocytes. Furthermore, less differentiated premature melanocytes (possibly melanoblasts) are probably more resistant to UV-induced apoptosis, which allows DNA damage to be fixed into mutations and hence triggers tumorigenesis. Human skin, even in older individuals, probably contains a portion of melanoblasts in the epidermis. In younger individuals, there are more melanoblasts in the epidermis, which is why overexposure to sunlight and tanning bed light at an early age increases the probability of developing melanoma. By contrast, mouse skin contains only mature melanocytes in the epidermis. UV can cause sunburn in these mice but not melanomagenesis.In summary, not all skins are equal and not all melanocytes are equal. Negative results in animal models of UVA-induced melanomagenesis should not negate the overwhelming evidence that UVA exposure increases the potential to trigger melanomagenesis in humans. We should avoid excessive sunlight and tanning bed exposure in order to reduce melanoma risk.AcknowledgementsThe author thanks Richard Setlow for his inspiration regarding the melanomagenesis research, and Hsiang-Tsui Wang, Neva Setlow and Bongkun Choi for their excellent research work.Financial & competing interests disclosureThis research was supported by the NIH grants CA114541, ES014641, CA99007 and ES00260. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.Bibliography1 Mitchell DL, Fernandez AA, Nairn RS et al.: Ultraviolet A does not induce melanomas in a Xiphophorushybrid fish model. Proc. Natl Acad. Sci. USA107(20),9329–9334 (2010).Crossref, Medline, CAS, Google Scholar2 Walker GJ, Kimlin MG, Hacker E et al.: Murine neonatal melanocytes exhibit a heightened proliferative response to ultraviolet radiation and migrate to the epidermal basal layer. J. Invest. 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USA90,6666–6670 (1993).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByBioengineered Efficacy Models of Skin Disease: Advances in the Last 10 Years28 January 2022 | Pharmaceutics, Vol. 14, No. 2Reactive Oxygen Species in Skin Repair, Regeneration, Aging, and Inflammation23 May 2018The skin microbiome and immune system: Potential target for chemoprevention?30 August 2017 | Photodermatology, Photoimmunology & Photomedicine, Vol. 34, No. 1Etiology22 December 2016UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden1 November 2012 | Photochemical & Photobiological Sciences, Vol. 11, No. 1The Response of Human Skin Commensal Bacteria as a Reflection of UV Radiation: UV-B Decreases Porphyrin Production25 October 2012 | PLoS ONE, Vol. 7, No. 10Malignant melanomas on head/neck and foot: differences in time and latitudinal trends in Norway28 June 2011 | Journal of the European Academy of Dermatology and Venereology, Vol. 26, No. 7UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden1 January 2012 | Photochem. Photobiol. Sci., Vol. 11, No. 1Does Melanoma Begin in a Melanocyte Stem Cell?Journal of Skin Cancer, Vol. 2012Significant Positive Correlation Between Sunshine and Lactase Nonpersistence in Europe May Implicate Both in Similarly Altering Risks for Some DiseasesNutrition and Cancer, Vol. 63, No. 7 Vol. 6, No. 10 eToC Sign up Follow us on social media for the latest updates Metrics History Published online 9 November 2010 Published in print October 2010 Information© Future Medicine LtdKeywordsDNA damageDNA repairmelanomaoxidativeultravioletAcknowledgementsThe author thanks Richard Setlow for his inspiration regarding the melanomagenesis research, and Hsiang-Tsui Wang, Neva Setlow and Bongkun Choi for their excellent research work.Financial & competing interests disclosureThis research was supported by the NIH grants CA114541, ES014641, CA99007 and ES00260. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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