Review article

Solar ultraviolet radiation from cancer induction to cancer prevention: solar ultraviolet radiation and cell biology Muobarak J. Tuorkey Although decades have elapsed, researchers still debate the benefits and hazards of solar ultraviolet radiation (UVR) exposure. On the one hand, humans derive most of their serum 25-hydroxycholecalciferol [25(OH)D3], which has potent anticancer activity, from solar UVB radiation. On the other hand, people are more aware of the risk of cancer incidence associated with harmful levels of solar UVR from daily sunlight exposure. Epidemiological data strongly implicate UV radiation exposure as a major cause of melanoma and other cancers, as UVR promotes mutations in oncogenes and tumor-suppressor genes. This review highlights the impact of the different mutagenic effects of solar UVR, along with the cellular and carcinogenic challenges with respect to sun exposure. European Journal

Background The ability of solar radiation to affect skin depends on the nature and properties of both light and skin. The sequences of changes in skin due to light exposure are induced by a photobiomodulation process. Light in the visible red to near-infrared range penetrates tissue well and activates endogenous photoreceptors, which in turn initiate light-altered signaling pathways (Abdul-Aziz and Tuorkey, 2010; Poyton and Ball, 2011). The mechanism of action of solar light depends on the absorption of photons by endogenous chromophores or melanin pigments in the melanosomes of melanocytes and keratinocytes. Recently, we concluded that mitochondrial cytochrome c oxidase can act as one of the endogenous photoreceptors (Abdul-Aziz and Tuorkey, 2010), which absorb part of the photon’s energy and convert it into heat that can be dissipated to neighboring tissue by conductivity (Zhang et al., 2003). Absorption of photonic energy by photon acceptor sites on the cell membrane elevates ATP production, and perturbs and changes the permeability of the cell membrane (Evans and Abrahamse, 2009). These changes could inhibit or accelerate several biological processes through the interaction of several intracellular signaling pathways. Recent findings provide important new insight for understanding the photomodulation effect of light (Gocke, 2001; Kurdykowski et al., 2012).

Part A: hazards of solar ultraviolet radiation

of Cancer Prevention 24:430–438 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. European Journal of Cancer Prevention 2015, 24:430–438 Keywords: melanoma of skin, nitric oxide, photoaging, sunbeds, ultraviolet signature mutations, vitamin D Department of Zoology, Division of Physiology, Faculty of Science, Damanhour University, Damanhour, Egypt Correspondence to Muobarak J. Tuorkey, PhD, Department of Physiology, Division of Physiology, Faculty of Science, Damanhour University, Damanhour, Egypt Tel: + 20 453 293 011; fax: + 20 453 368 757; e-mail: [email protected] Received 14 May 2013 Accepted 27 May 2015

the skin, asymmetrical pigmentation (including freckles), and inelasticity (Bhawan et al., 1995; Binic et al., 2013). Thus, aged skin exhibits both a yellowish hue because of hyperpigmentation and a leathery texture (Buechner et al., 2008). Furthermore, researchers have also reported a reduction in dermal collagen levels and an increase in the expression of matrix metalloproteinase-1 (MMP-1) in aged skin (Fligiel et al., 2003). Recently, MMP-1 and collagen type Iα1 were reported to be affected by ultraviolet A (UVA; wavelength of 320–400 nm), UVB (wavelength of 280–320 nm), and infrared wavelengths; thus, these spectra of light are involved in photoaging (Buechner et al., 2008). In fact, UVA acquires its ability to modulate MMP expression through transcriptional activation of activator protein 1 signaling (Kim et al., 2013). UVB could affect angiogenesis and initiate lymphatic dysfunction in the skin (Sawane and Kajiya, 2012). Another major signaling pathway for photoaging is the formation of reactive oxygen species (ROS; Olah et al., 2012; Dupont et al., 2013). Because of its ability to stimulate ROS production, UV radiation (UVR) is involved in mutagenesis and photoaging (Situm et al., 2010; Dupont et al., 2013). Neutrophils have also been speculated to play a role in photoaging, as they infiltrate the skin and release enzymatically active elastases, including neutrophil elastase, collagenase (MMP-1), and gelatinase (MMP-9; Rijken et al., 2005). Moreover, neutrophils are the major producers of proteolytic substances, including MMP-8, pluripotent neutrophil elastase, and MMP-9 (Foerster et al., 2006).


Photoaging caused by chronic sun exposure is characterized by dermal connective tissue changes, dryness of 0959-8278 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Finally, activation of specific cytokines could be a further possible mechanism of photoaging. For instance, DOI: 10.1097/CEJ.0000000000000181

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Solar UV and cancer Tuorkey 431

interleukin 6 (IL-6) mediates the collagenolytic activity initiated by the UV-induced and infrared-induced stimulation of MMP-1 (Binic et al., 2013). Tumor necrosis factor α (TNF-α) has been recognized as a potent inhibitor of connective tissue formation (Westermarck et al., 1995; Lamprecht, 2005). The cellular effect of TNF-α is mediated by two distinct cell-surface receptors, TNFR55 and TNF-R75, both of which are present on various types of cell, including fibroblasts. Thus, TNF-α may afflict collagen synthesis in human skin, at least in part through the activation of TNF-R55 (Westermarck et al., 1995). Solar ultraviolet radiation and the eye

Little is known about the toxic effect of solar UVR on the human eye, as conducting such studies on human participants is problematic. Thus, quantifying the impact of avoidance and protective mechanisms in the context of corneal trauma, pterygium, and cataracts is quite difficult. Even though ocular tissues have an antioxidant defense system that serves to eliminate ROS and protect the eye from oxidative damage (Marchitti et al., 2011), UVR can impair several of this system’s antioxidant enzymes. For instance, unilateral exposure to 8 kJ/m2 of 300 nm UVR for 15 min significantly depleted lens glutathione in rats (Wang et al., 2011). Galichanin et al. (2012) experimentally showed how UVB could induce cataracts in animals. In one important study, a manikin eye was exposed to solar UVR at different rotation angles in relation to the sun at different solar elevation angles (Hu et al., 2013). The study concluded that when the solar elevation angle is 40°, maintaining certain orientations in relation to the sun’s position could effectively reduce ocular UVR exposure. Mechanisms of ultraviolet radiation-induced immunosuppression

The study by Halliday et al. (2012) offered new insight into the mechanism by which UVR suppresses skin immunity. UVR causes an energy crisis in the epidermis that inhibits glycolysis and decreases the levels of ATP (Park et al., 2010; Surjana et al., 2013). However, supplementation with NAD, which is metabolized to NAD+ and acts as a coenzyme for ATP production, could prevent such energy loss in keratinocytes. Therefore, both topical and oral NAD could prevent UV-induced suppression of recall immunity in humans (Sivapirabu et al., 2009; Yiasemides et al., 2009). However, vitamin D (a UVB photoproduct) remains the superior systemic immunomodulator. A direct regulatory role of 1α,25 (OH)2D3 (the active form of vitamin D) has been investigated in the gene transcription of various cytokines, including IL-12 (D’Ambrosio et al., 1998), IL-2 (Takeuchi et al., 1998), interferon-γ (IFN-γ) (Cippitelli and Santoni, 1998), granulocyte–macrophage colonystimulating factor (GM-CSF; Towers and Freedman, 1998), IL-8 (Harant et al., 1997), IL-4 (Cantorna et al.,

1998), and transforming growth factor β (TGF-β; Staal et al., 1996). Such an effect is initiated through the interaction of vitamin D with the nuclear factor-κB (NFκB)-responsive elements of the activated T cells or activator protein 1 sites in the respective promoter regions. The regulatory effect of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] is attributed to its inhibition of IL-12 produced by antigen-presenting cells (activated macrophages), in addition to its ability to block the accumulation of mRNAs for IL-2, IFN-γ, and GM-CSF (Thomasset, 1994). Ultraviolet radiation-induced inflammation and cytokine production

Upregulation of TNF-α is a key early response to UVB radiation exposure in keratinocytes and a key mediator for triggering the inflammatory cascade in the skin. UVB irradiation induces TNF-α expression in both keratinocytes and dermal fibroblasts. Surprisingly, TNF-α mRNA induction has been seen as early as 1.5 h after UVB exposure (Silveira et al., 2013). Such an immediate reaction also extends to the epidermal keratinocytes and mediates the release of proinflammatory cytokines such as IL-1 and IL-6 (Bashir et al., 2009b, 2009a). In addition, UVR exposure upregulates mRNA expression of cyclooxygenase 2 (Rhodes et al., 2001) and inducible nitric oxide (NO) synthase in epidermal keratinocytes, which in turn trigger prostaglandin E2 and NO syntheses. These two chemical mediators increase melanogenesis of melanocytes in vitro. The levels of cyclooxygenase 2 mRNA and prostaglandin E2 increase after a low dose of UVB irradiation in vitro (Kuwamoto et al., 2000). Although UVB radiation induces secretion of not only IL-1, IL-6, and TNF-α but also IL-10 and IL-12, UVA radiation induces secretion of only IL-10, produced mainly by dermal CD11b + macrophages and neutrophils that infiltrate the epidermis after intense UV exposure (Boonstra et al., 2000). IL-10 can suppress T-cell-mediated immune response and thus could induce an immune tolerance to neoantigens. Conversely, IL-12 can reverse such immune tolerance through its ability to reduce immunosuppression due to UVR exposure (Ando et al., 2000).

Part B: role and mechanisms of solar ultraviolet radiation in cancer development Ultraviolet radiation-induced oxidation of DNA dimer base

Absorbance of UVA by DNA is very weak (Pustisek and Situm, 2011); thus, the mutagenic effect of UVA could be attributed to the photo-oxidation products of guanine, including 8-hydroxydeoxyguanosine (8-OHdG), which may be responsible for G–C to C–G base-pair transversions (Kino and Sugiyama, 2005; Kozmin et al., 2005). In fact, the level of 8-OHdG formed by UVA radiation exposure was approximately three-fold that formed by UVB exposure (Douki et al., 1999). Furthermore, DNA

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432 European Journal of Cancer Prevention 2015, Vol 24 No 5

lesions formed due to UVR exposure are characterized by elevated amounts of cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (Setlow and Carrier, 1966; Mitchell, 1988; Mitchell and Nairn, 1989). The following guidelines were used to distinguish between the damage that could be induced by UVB and UVA: UVB primarily yields CPDs and pyrimidine (6–4) pyrimidone photoproducts (6–4PP) with minor amounts of 8-OHdG (Mouret et al., 2010); by contrast, UVA primarily leads to oxidative DNA damage by producing 8-OHdG with minor amounts of CPDs (most commonly T = T dimers; Beehler et al., 1992). Neither visible nor infrared radiation has been shown to produce CPDs, 6–4PP, or 8-OHdG (Rochette et al., 2003). Ultraviolet radiation–oxidative stress mediation

At least 50% of UVB-induced damage is attributable to the formation of ROS. ROS are generated by the transfer of electromagnetic energy from UVB radiation to molecular oxygen (Elsner et al., 2007; Wolfle et al., 2011). Furthermore, exposure of skin cells to UVB induces an immediate release of labile iron (Brenneisen et al., 1998), which can catalyze the highly toxic hydroxyl radical (OH–) through the Fenton reaction (Kruszewski, 2003). In support of this notion, UVA-induced iron-dependent and 1O2-dependent oxidative damage to lipids and proteins has been observed in vitro and in human skin fibroblasts (Vile et al., 1995). In addition, Wei et al. (2002) showed that H2O2 is a part of the acute skin response to UVB exposure and can be generated by keratinocytes and infiltrating neutrophils in the skin of hairless mice. However, chronic exposure of mice to low-dose UVB (0.9–1.2 kJ/m2 for 20 weeks) augmented the levels of 8-OHdG not only in the epidermis but also in the internal organs, including the liver, brain, and spleen, with the exception of the kidney (Wei et al., 2002). Thus, one could speculate that under these conditions, H2O2 is generated during the acute cutaneous response to UVB irradiation, whereas lipid peroxidation and 8-OHdG accumulation occur later as a chronic response to UVB radiation. Solar ultraviolet radiation signature mutations in melanoma

Solar UVR, particularly UVA rather than UVB, has been well recognized as a major cause for the development of both melanoma and nonmelanoma skin cancers (Moan et al., 1999; Wang et al., 2001). However, even this assertion has been questioned, as only UVB, but not UVA, induced melanoma in a transgenic mouse model (De Fabo et al., 2004). The mutagenic effect of UVR gained from the direct absorption of solar UV photons by DNA could be the origin of some genotoxic dipyrimidine photoproducts, including cis-syn CPDs and 6–4PP. Thus, UVA mutagenesis emerges from oxidative DNA-base modifications (Darr and Fridovich, 1994; Kielbassa et al., 1997; Stary and Sarasin, 2000). Many adenine-to-cytosine

(A–C) transversions in hamster cells have been investigated in the UVA spectrum, but not with UVB; such mutations are fingerprints of exposure to UVA (Drobetsky et al., 1995). Most of these mutations were found to be cytosine-to-thymine (C–T) transitions in both UVA and UVB spectra. These transitions also included CC-to-TT tandem mutations. A recent study indicated that Hupki mice exposed to UVB light at a chronic dose (4.5 kJ/m2 five times/week for 4 weeks) harbor C–T and CC–TT mutations at two mutation hotspots that are also identified in human skin cancer (Luo et al., 2001; Kappes et al., 2006). This implies, at least in part, that a high proportion of mutations are typically generated by mispairing of the template 8-oxoG with guanine-to-thymine (G–T) transversions, or by misincorporation as the substrate opposite A–C transversions (Epe, 1991; Cheng et al., 1992). However, at least 25% of UVA-induced mutations in rodent cells were recorded to be G–T transversions (Besaratinia et al., 2004). Three G–T transversions in the p53 gene of single keratinocytes derived from UVA-irradiated human skin have been recorded (Persson et al., 2002). Taken together, UVA genotoxic dipyrimidine photoproducts and oxygen radical-induced DNA strand breaks could aggregate mutations after UVA-induced oxidative stress (Peak et al., 1987).

Part C: benefits of solar ultraviolet radiation Ultraviolet radiation-triggered nitric oxide release

NO is a potent vasodilator that activates the generation of cGMP, the superior effector in NO-induced vasorelaxation in various tissues (Zembowicz et al., 1992). In fact, NO is synthesized from the amino acid L-arginine by NO synthase (Moncada et al., 1991). The conversion of L-arginine to NO by the isoforms of NO synthase is well defined. NG hydroxylation of L-arginine (L-HOArg) is the first step in the biosynthesis of NO by macrophages (Marletta et al., 1988; Stuehr et al., 1990, 1991). NO produced by UVA-irradiated keratinocytes stimulates melanogenesis of melanocytes in vitro (Romero-Graillet et al., 1997). UVA-derived NO fully protects endothelial cells against apoptosis or necrosis during or after UVA exposure (Suschek et al., 1999, 2001, 2003). For instance, L-arginine, the substrate of the NO synthases, increases the deleterious effect of UVA irradiation (Didier et al., 1999). In addition, the NO donor S-nitrosocysteine can protect endothelial cells from UVA-induced oxidative damage (Suschek et al., 2001). It is a very apt notion that low concentrations of NO donors stimulate the proliferation of primary keratinocytes, whereas high concentrations cause cytostatic effects (Krischel et al., 1998). Beckman and Koppenol (1996) have explained in detail such opposite results of the effects of NO on cells. However, to summarize, NO competes with most intercellular messengers owing to its rapid and isotropic diffusion through most tissues with limited reaction, and it cannot pass further through blood vasculature because of

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Solar UV and cancer Tuorkey 433

its rapid destruction by oxyhemoglobin. The ability of NO to diffuse through cells allows it to pass through the epithelial layers of blood vessels and reach the bloodstream. Thus, it can reach the synapses and modulate neuronal transmission, thereby controlling the oscillatory behavior of neuronal networks. NO is removed by red blood cells within seconds after reaching tissues, through interaction with oxyhemoglobin. Neutrophils, macrophages, neurons, and endothelial cells can produce both O2– and NO– through the respective actions of various oxidases and NO synthases. Taken together, O2– reacts extremely rapidly with NO– and yields peroxynitrite (ONOO–)/peroxynitrous acid (ONOOH), which is a strong general oxidant and nitrating agent. NO has little direct toxicity; however, it reacts with superoxide radicals to form the more toxic form, peroxynitrite (ONOO–). Peroxynitrite interacts with most cellular molecules to yield a nitrative stress, which can modify tyrosine in proteins to create nitrotyrosines in vivo (Beckman and Koppenol, 1996). In human skin, topical application of NO leads to the accumulation of p53, followed by apoptosis (Ormerod et al., 1999).

1998; IFN-γ, GM-CSF, Towers and Freedman, 1998; IL-8, Harant et al., 1997; TNF-α, Lemire, 1992; and TGF-β, Staal et al., 1996) could explain how vitamin D prolongs cellular lifespan. Vitamin D receptors (VDRs) are ubiquitously expressed in T cells and natural killer cells, B lymphocytes, and monocytes (Deluca and Cantorna, 2001; Mathieu and Adorini, 2002). Through the downregulation of several cytokines, vitamin D exerts anti-inflammatory and antiproliferative abilities (Nagpal et al., 2005). In support of this notion, a large population-based cohort study found that women with higher serum vitamin D concentrations had longer telomeres in leukocytes (Richards et al., 2007).

Part D: role of solar ultraviolet B radiation in prevention of melanoma Epidemiology

Many epidemiological as well as in-vitro and in-vivo laboratory studies have emphasized the antioxidative properties of vitamin D (Bandeira et al., 2006; Rondanelli et al., 2007; Bao et al., 2008). For instance, 1,25-(OH)2D3 could eliminate ROS in cultured nonmalignant prostate cells through transcriptional activation of glucose6-phosphate dehydrogenase (Bandeira et al., 2006; Bao et al., 2008). In addition, 1,25-(OH)2D3 can modulate several signaling pathways, including FoxO, mitogenactivated protein kinase (MAPK), JAK-STAT, p53, phospholipase C, JNK, and PI3K, in mice (Houstis et al., 2006).

The protective effects of vitamin D against carcinogenesis have led to speculation that regions with higher solar UVB irradiation may have higher rates of cancer survival. Many such countries are located at mid latitude and could clarify this speculation, but the lack of cancer registries in developing countries prevents follow-up on this trend. To assist with exploring the relationship between latitudes and the incidence rates of melanoma, the incidence rates for both male and female skin cancer in 2008 against latitude for 19 countries have been plotted in Fig. 1. Multiple linear regression analysis was carried out using sigma plot 10 (Systat Software Inc., San Jose, California, USA) and Prism 3.0 package (GraphPad Software, San Diego, California, USA). The regression assessed the relationship between the incidence rates of melanoma on the basis of the sex of the patients. Data on skin cancer patients by country were obtained from the GLOBOCAN database (http://globocan. iarc.fr/). The data confirm that male and female individuals living in the highest-latitude countries had the highest rates of skin melanoma (r2 = 0.56, P = 0.004, and r2 = 0.63, P = 0.002, respectively); thus, the rate of incidence is positively correlated with latitude. Conversely, in low-latitude countries the incidence rate of skin melanoma was negatively associated with latitude for male and female individuals (r2 = 0.49, P = 0.0770, and r2 = 0.50, P = 0.0727, respectively), although the effect was not statistically significant. Recently, a population-based cohort study by Chen et al. (2013) confirmed that exposure to UVB was prominently associated with the mortality-to-incidence ratio of the 10 most common cancer types (Chen et al., 2013). The mortality-to-incidence ratios had a hazard ratio of 0.96 (95% confidence interval, 0.93–0.99) for men and 0.91 (95% confidence interval, 0.88–0.94) for women. Therefore, the authors have speculated that solar UVB may increase the survival rate for some cancers, at least in part, in China.

Increases in cellular lifespan

A molecular study

The potency of vitamin D to mediate immune suppression of several cytokines and proinflammatory mediators (e.g. IL-12, D’Ambrosio et al., 1998; IL-2, Takeuchi et al.,

Today, great attention has been directed toward the incidence and prognosis of certain cancers and their correlation with low levels of serum 25(OH)D3 (Luo

Solar ultraviolet radiation provides cellular therapy

UVB therapy (particularly narrow band) may be much a better treatment than drugs for itch in uremia (Twycross et al., 2003). Individual dosing of natural UVR combined with clinical determination of variations of skin lesions in patients with psoriasis vulgaris yielded a good correlation between UVR dose and the rate of healing (Walther et al., 1989). UV-receptor activation of NF-κB in Langerhans cells can induce antiapoptotic and prosurvival signals by hyperactivation of Bcl-xL (Lee et al., 2013). In addition, a therapeutic dosage of UV could arrest the cell cycle and mediate apoptosis through translocation of Bcl-2 family proteins, which in melanocytes ensure survival and genomic integrity (Lee et al., 2013). Vitamin D other than immune modulation Free radical-scavenging activities

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434 European Journal of Cancer Prevention 2015, Vol 24 No 5

Fig. 1

(a) 100

Incidence rate of melanoma of skin per 100 000


Australia 40

Male, r 2 = 0.5699, P = 0.004 Female, r 2 = 0.6307, P = 0.002

40 30

Incidence rate per 100 000

Male Female


Male, r 2 = 0.4967, P = 0.0770 Female, r 2 = 0.5068, P = 0.0727


20 10

−100 0

New Zealand −10

−200 −50 −25






100 125











Israel Argentina Chile

Brazil Angola

Germany Austria


Nigeria Sudan Egypt

0 Namibia









Latitude The correlation between latitude and the incidence rates of melanoma of the skin in both men and women in 19 countries located at (a) low latitude and (b) high latitude. GLOBOCAN database, 2008.

et al., 2012). Recently, PDZ-LIM domain-containing protein 2 (PDLIM2) was found to be repressed in human breast cancer cells because of hypermethylation of the regulatory promoter regions, which in turn increases tumorigenicity (Vanoirbeek et al., 2013). Evidence indicates that 1,25(OH)2D3 can demethylate the PDLIM2 promoter and suppress cancer cell invasion. Moreover, an in-vivo study confirmed that dietary vitamin D3 significantly inhibits tumor activity in xenograft models of breast cancer (Krishnan et al., 2012a). This effect is to due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in all cells, including breast cells. CYP27B1 acts naturally to convert circulatory 25-hydroxyvitamin D to the more active form, calcitriol, which occurs locally within the breast microenvironment; therefore, it can act in a paracrine manner to inhibit breast cancer cell growth (Krishnan et al., 2012b). However, that mechanism depends on the efficiency and bioavailability of VDRs; hence, some cancers abolish the function of VDRs and thus deter the antioncogenetic effect of 1,25(OH)2D3. In support of this notion, the ras activation of MAPK makes keratinocytes unresponsive to the inhibitory effect of 1,25(OH)2D3. MAPK can phosphorylate RXRα, which in

turn prevents the binding of RXRα to its respective VDR. Recently, both the NF-κB receptor activator, RANK, and its ligand, RANKL, have been speculated to be key regulators of the skin’s immune function by affecting epidermal dendritic cells and T-regulatory cells upon UVR exposure (Loser et al., 2006). Such a finding is interesting because vitamin D, which is generated in the skin upon UVB exposure, is the strongest inducer of RANKL expression.

Time trends An individual’s level of exposure to UV varies with type of skin, latitude, altitude, time of year, time of day, and atmospheric components, including clouding of the sky and air pollution. In addition, the ability of UVB radiation to mediate skin erythema is ~ 103–104 times higher than that of UVA (Juzeniene and Moan, 2012). Thus, determining how long to sunbathe to derive enough 25(OH) D3 from solar UVB radiation is complicated. But in fact, exposing 15% of the body (e.g. hands, face, and arms) to one minimal erythemal dose (the minimal amount of energy required to produce a qualifying erythemal response, usually after 24 h) on most days of the week is equivalent to an intake of 1000 IU (equivalent to 25 mg;

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Solar UV and cancer Tuorkey 435

Alpert and Shaikh, 2007). Such erythemal response could be in the form of a perceptible reddening or uniform redness with clearly demarcated borders on the skin. Unfortunately, one billion individuals worldwide have either vitamin D deficiency [ < 20 ng/ml (50 nmol/l)] or insufficiency [21–29 ng/ml (52–72 nmol/l)] (Holick, 2006). This figure is not only restricted to those countries located at high latitude, but extends also to the sunniest areas of the world, where people probably avoid UVR to avoid the carcinogenic effect of sunlight exposure (melanoma). The latter could explain the incidence rate of melanoma in these countries located at lower latitude.

modulate neuronal transmissions. NO can thus control the oscillatory behavior of neuronal networks that could improve mood and neurotolerance. That is all aside from the crucial role of UVB in vitamin D biosynthesis. The latter is stringently essential for many cellular pathways and for immune modulation; it also has the ability to compete with ROS generated on solar UVR exposure. Nowadays, sunbeds are widely used as an alternative vitamin D source, instead of solar UVB, among those living in northern Europe and the highest-latitude countries. However, as using sunbeds increases the risk of melanoma incidence, strict regulations governing sunbed use are required.


Figure 2 summarizes the hazardous effects of solar UVR. UVR interacts with different endogenous chromophores in the skin (e.g. cytochrome c of the mitochondria, flavins, NADH/NADPH, and urocanic acid) and produces ROS. Upon UVA exposure, UVA-induced irondependent and 1O2-dependent oxidative damage to lipids and proteins occurs (Vile et al., 1995), whereas UVB exposure generates H2O2 during the acute skin response (Wei et al., 2002). Thus, because of its greater ROSproducing potency, particularly singlet oxygen (1O2), UVA is more mutagenic than UVB. In support of this assertion, the level of 8-OHdG was reported to be approximately three-fold higher upon UVA exposure than upon UVB exposure. The immunoprotective effect of UV could be attributed to photo-oxidation products, including vitamin D, inhibition of glycolysis, and attenuated ATP production (Park et al., 2010; Surjana et al., 2013). However, the beneficial effect of UVR exposure stems from its ability to induce NO release, which can


The results of studies on melanoma of the skin may be germane to other hereditary diseases and/or other environmental toxic insults. The multiple linear regression model assessed the relationship between latitudes and the incidence rates of melanoma. However, it is more appropriate to correlate the levels of either UVA or UVB in each latitude to define the real effect of solar UVR on cancer genesis and/or prevention. The correlation between smoking and risk for melanoma is not determined or demonstrated in this review. Despite its role in lung cancer induction, smoking is widely documented to be inversely correlated with the development of melanoma of the skin. The generated free radicals from cigarette smoking accelerate the processes of skin aging and increase skin wrinkling through elastosis. The latter is suggested as the mechanism through which smoking reduces the risk for melanoma (Grant, 2012).

Fig. 2

Chromophores Cytochrome c Flavins NADH/NADPH Urocanic acid

1O 2

H2O2 OH−

Solar UVR

Immunosuppression neuromodulation


ONOO− Peroxynitrite

ONOO H+ Peroxynitrous

NO2− Nitrite


Single-strand breaks DNA—protein crosslinks

Cytokine release Thymine dimer formation Immunosuppression Macrophage and neutrophil infiltration

DNA damage 8-OHdG (UVA major) CPDs (UVB major) 6 − 4PP (both UVA and UVB)

Mutations DNA Tumor suppressor gene p53

UV radiation mediates DNA damage, oxidative stress, and immunosuppression in the skin. CPDs, cyclobutane pyrimidine dimers; NO, nitric oxide; 8-OHdG, 8-hydroxydeoxyguanosine; 6–4PP, pyrimidine (6–4) pyrimidone photoproducts; UV, ultraviolet; UVR, ultraviolet radiation.

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436 European Journal of Cancer Prevention 2015, Vol 24 No 5

Acknowledgements The author thanks Dr William B. Grant for insightful discussions and corrections during revision of the revised manuscript. The author also thanks Mr Gabe Waggoner for editing the revised manuscript. Conflicts of interest

There are no conflicts of interest.

References Abdul-Aziz KK, Tuorkey MJ (2010). Argon laser phototherapy could eliminate the damage effects induced by the ionizing radiation “gamma radiation” in irradiated rabbits. J Photochem Photobiol B 99:29–35. Alpert PT, Shaikh U (2007). The effects of vitamin D deficiency and insufficiency on the endocrine and paracrine systems. Biol Res Nurs 9:117–129. Ando O, Suemoto Y, Kurimoto M, Horikawa T, Ichihashi M (2000). Deficient Th1-type immune responses via impaired CD28 signaling in ultraviolet B-induced systemic immunosuppression and the restorative effect of IL-12. J Dermatol Sci 24:190–202. Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, Freese E (2006). Vitamin D deficiency: a global perspective. Arq Bras Endocrinol Metabol 1950: 640–646. Bao BY, Ting HJ, Hsu JW, Lee YF (2008). Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer 122:2699–2706. Bashir MM, Sharma MR, Werth VP (2009a). TNF-alpha production in the skin. Arch Dermatol Res 301:87–91. Bashir MM, Sharma MR, Werth VP (2009b). UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. J Invest Dermatol 129:994–1001. Beckman JS, Koppenol WH (1996). Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437. Beehler BC, Przybyszewski J, Box HB, Kulesz-Martin MF (1992). Formation of 8-hydroxydeoxyguanosine within DNA of mouse keratinocytes exposed in culture to UVB and H2O2. Carcinogenesis 13:2003–2007. Besaratinia A, Synold TW, Xi B, Pfeifer GP (2004). G-to-T transversions and small tandem base deletions are the hallmark of mutations induced by ultraviolet a radiation in mammalian cells. Biochemistry 43:8169–8177. Bhawan J, Andersen W, Lee J, Labadie R, Solares G (1995). Photoaging versus intrinsic aging: a morphologic assessment of facial skin. J Cutan Pathol 22:154–159. Binic I, Lazarevic V, Ljubenovic M, Mojsa J, Sokolovic D (2013). Skin ageing: natural weapons and strategies. Evid Based Complement Alternat Med 2013:827248. Boonstra A, van Oudenaren A, Barendregt B, An L, Leenen PJ, Savelkoul HF (2000). UVB irradiation modulates systemic immune responses by affecting cytokine production of antigen-presenting cells. Int Immunol 12:1531–1538. Brenneisen P, Wenk J, Klotz LO, Wlaschek M, Briviba K, Krieg T, et al. (1998). Central role of ferrous/ferric iron in the ultraviolet B irradiation-mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metalloprotease (MMP)-1) and stromelysin-1 (MMP-3) mRNA levels in cultured human dermal fibroblasts. J Biol Chem 273:5279–5287. Buechner N, Schroeder P, Jakob S, Kunze K, Maresch T, Calles C, et al. (2008). Changes of MMP-1 and collagen type Ialpha1 by UVA, UVB and IRA are differentially regulated by Trx-1. Exp Gerontol 43:633–637. Cantorna MT, Hullett DA, Redaelli C, Brandt CR, Humpal-Winter J, Sollinger HW, Deluca HF (1998). 1,25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. Transplantation 66:828–831. Chen W, Armstrong BK, Rahman B, Zheng R, Zhang S, Clements M (2013). Relationship between cancer survival and ambient ultraviolet B irradiance in China. Cancer Causes Control 21:1701–1709. Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA (1992). 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions. J Biol Chem 267:166–172. Cippitelli M, Santoni A (1998). Vitamin D3: a transcriptional modulator of the interferon-gamma gene. Eur J Immunol 28:3017–3030. D’Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A, Sinigaglia F (1998). Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol 161:5111–5115. Darr D, Fridovich I (1994). Free radicals in cutaneous biology. J Invest Dermatol 102:671–675.

De Fabo EC, Noonan FP, Fears T, Merlino G (2004). Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res 64:6372–6376. Deluca HF, Cantorna MT (2001). Vitamin D: its role and uses in immunology. FASEB J 15:2579–2585. Didier C, Emonet-Piccardi N, Beani JC, Cadet J, Richard MJ (1999). L-arginine increases UVA cytotoxicity in irradiated human keratinocyte cell line: potential role of nitric oxide. FASEB J 13:1817–1824. Douki T, Perdiz D, Grof P, Kuluncsics Z, Moustacchi E, Cadet J, Sage E (1999). Oxidation of guanine in cellular DNA by solar UV radiation: biological role. Photochem Photobiol 70:184–190. Drobetsky EA, Turcotte J, Chateauneuf A (1995). A role for ultraviolet A in solar mutagenesis. Proc Natl Acad Sci USA 92:2350–2354. Dupont E, Gomez J, Bilodeau D (2013). Beyond UV radiation: a skin under challenge. Int J Cosmet Sci 35:224–232. Elsner P, Holzle E, Diepgen T, Grether-Beck S, Honigsmann H, Krutmann J, et al. (2007). Recommendation: daily sun protection in the prevention of chronic UV-induced skin damage. J Dtsch Dermatol Ges 5:166–173. Epe B (1991). Genotoxicity of singlet oxygen. Chem Biol Interact 80:239–260. Evans DH, Abrahamse H (2009). A review of laboratory-based methods to investigate second messengers in low-level laser therapy (LLLT). Med Laser Appl 24:201–215. Fligiel SE, Varani J, Datta SC, Kang S, Fisher GJ, Voorhees JJ (2003). Collagen degradation in aged/photodamaged skin in vivo and after exposure to matrix metalloproteinase-1 in vitro. J Invest Dermatol 120:842–848. Foerster J, Storch A, Fleischanderl S, Wittstock S, Pfeiffer S, Riemekasten G, Worm M (2006). Neutrophil respiratory burst is decreased in scleroderma and normalized by near-infrared mediated hyperthermia. Clin Exp Dermatol 31:799–806. Galichanin K, Talebizadeh N, Soderberg P (2012). Characterization of molecular mechanisms of in vivo UVR induced cataract. J Vis Exp e4016. Gocke E (2001). Photochemical mutagenesis: examples and toxicological relevance. J Environ Pathol Toxicol Oncol 20:285–292. Grant WB (2012). On the roles of solar UV irradiance and smoking on the diagnosis of second cancers after diagnosis of melanoma. Dermatoendocrinol 4:12–17. Halliday GM, Damian DL, Rana S, Byrne SN (2012). The suppressive effects of ultraviolet radiation on immunity in the skin and internal organs: implications for autoimmunity. J Dermatol Sci 66:176–182. Harant H, Andrew PJ, Reddy GS, Foglar E, Lindley IJ (1997). 1alpha,25-dihydroxyvitamin D3 and a variety of its natural metabolites transcriptionally repress nuclear-factor-kappaB-mediated interleukin-8 gene expression. Eur J Biochem 250:63–71. Holick MF (2006). Resurrection of vitamin D deficiency and rickets. J Clin Invest 116:2062–2072. Houstis N, Rosen ED, Lander ES (2006). Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 13:944–948. Hu L, Gao Q, Gao N, Liu G, Wang Y, Gong H, Liu Y (2013). Solar UV exposure at eye is different from environmental UV: diurnal monitoring at different rotation angles using a manikin. J Occup Environ Hyg 10:17–25. Juzeniene A, Moan J (2012). Beneficial effects of UV radiation other than via vitamin D production. Dermatoendocrinol 4:109–117. Kappes UP, Luo D, Potter M, Schulmeister K, Runger TM (2006). Short- and longwave UV light (UVB and UVA) induce similar mutations in human skin cells. J Invest Dermatol 126:667–675. Kielbassa C, Roza L, Epe B (1997). Wavelength dependence of oxidative DNA damage induced by UV and visible light. Carcinogenesis 18:811–816. Kim JA, Ahn BN, Kong CS, Kim SK (2013). The chromene sargachromanol E inhibits ultraviolet A-induced ageing of skin in human dermal fibroblasts. Br J Dermatol 168:968–976. Kino K, Sugiyama H (2005). UVR-induced G–C to C–G transversions from oxidative DNA damage. Mutat Res 571:33–42. Kozmin S, Slezak G, Reynaud-Angelin A, Elie C, de Rycke RY, Boiteux S, Sage E (2005). UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 102:13538–13543. Krischel V, Bruch-Gerharz D, Suschek C, Kroncke KD, Ruzicka T, Kolb-Bachofen V (1998). Biphasic effect of exogenous nitric oxide on proliferation and differentiation in skin derived keratinocytes but not fibroblasts. J Invest Dermatol 111:286–291. Krishnan AV, Swami S, Feldman D (2012a). Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention. J Steroid Biochem Mol Biol 136:289–295. Krishnan AV, Swami S, Feldman D (2012b). The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer. Steroids 77:1107–1112.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Solar UV and cancer Tuorkey 437

Kruszewski M (2003). Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res 531:81–92. Kurdykowski S, Mine S, Bardey V, Danoux L, Jeanmaire C, Pauly G, et al. (2012). Ultraviolet-B irradiation induces epidermal up-regulation of heparanase expression and activity. J Photochem Photobiol B 106:107–112. Kuwamoto K, Miyauchi-Hashimoto H, Tanaka K, Eguchi N, Inui T, Urade Y, Horio T (2000). Possible involvement of enhanced prostaglandin E2 production in the photosensitivity in xeroderma pigmentosum group A model mice. J Invest Dermatol 114:241–246. Lamprecht P (2005). TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases. Autoimmun Rev 4:28–34. Lee CH, Wu SB, Hong CH, Yu HS, Wei YH (2013). Molecular mechanisms of UV-induced apoptosis and its effects on skin residential cells: the implication in UV-based phototherapy. Int J Mol Sci 14:6414–6435. Lemire JM (1992). Immunomodulatory role of 1,25-dihydroxyvitamin D3. J Cell Biochem 49:26–31. Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, et al. (2006). Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 12:1372–1379. Luo JL, Tong WM, Yoon JH, Hergenhahn M, Koomagi R, Yang Q, et al. (2001). UVinduced DNA damage and mutations in Hupki (human p53 knock-in) mice recapitulate p53 hotspot alterations in sun-exposed human skin. Cancer Res 61:8158–8163. Luo W, Hershberger PA, Trump DL, Johnson CS (2012). 24-Hydroxylase in cancer: impact on vitamin D-based anticancer therapeutics. J Steroid Biochem Mol Biol 136:252–257. Marchitti SA, Chen Y, Thompson DC, Vasiliou V (2011). Ultraviolet radiation: cellular antioxidant response and the role of ocular aldehyde dehydrogenase enzymes. Eye Contact Lens 37:206–213. Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS (1988). Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry 27:8706–8711. Mathieu C, Adorini L (2002). The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 8:174–179. Mitchell DL (1988). The relative cytotoxicity of (6–4) photoproducts and cyclobutane dimers in mammalian cells. Photochem Photobiol 48:51–57. Mitchell DL, Nairn RS (1989). The biology of the (6–4) photoproduct. Photochem Photobiol 49:805–819. Moan J, Dahlback A, Setlow RB (1999). Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol 70:243–247. Moncada S, Palmer RM, Higgs EA (1991). Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142. Mouret S, Philippe C, Gracia-Chantegrel J, Banyasz A, Karpati S, Markovitsi D, Douki T (2010). UVA-induced cyclobutane pyrimidine dimers in DNA: a direct photochemical mechanism? Org Biomol Chem 8:1706–1711. Nagpal S, Na S, Rathnachalam R (2005). Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687. Olah A, Szollosi AG, Biro T (2012). The channel physiology of the skin. Rev Physiol Biochem Pharmacol 163:65–131. Ormerod AD, Copeland P, Hay I, Husain A, Ewen SW (1999). The inflammatory and cytotoxic effects of a nitric oxide releasing cream on normal skin. J Invest Dermatol 113:392–397. Park J, Halliday GM, Surjana D, Damian DL (2010). Nicotinamide prevents ultraviolet radiation-induced cellular energy loss. Photochem Photobiol 86: 942–948. Peak MJ, Peak JG, Carnes BA (1987). Induction of direct and indirect singlestrand breaks in human cell DNA by far- and near-ultraviolet radiations: action spectrum and mechanisms. Photochem Photobiol 45:381–387. Persson AE, Edstrom DW, Backvall H, Lundeberg J, Ponten F, Ros AM, Williams C (2002). The mutagenic effect of ultraviolet-A1 on human skin demonstrated by sequencing the p53 gene in single keratinocytes. Photodermatol Photoimmunol Photomed 18:287–293. Poyton RO, Ball KA (2011). Therapeutic photobiomodulation: nitric oxide and a novel function of mitochondrial cytochrome c oxidase. Discov Med 11: 154–159. Pustisek N, Situm M (2011). UV-radiation, apoptosis and skin. Coll Antropol 35 (Suppl 2):339–341. Rhodes LE, Belgi G, Parslew R, McLoughlin L, Clough GF, Friedmann PS (2001). Ultraviolet-B-induced erythema is mediated by nitric oxide and prostaglandin E2 in combination. J Invest Dermatol 117:880–885. Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, et al. (2007). Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr 86:1420–1425.

Rijken F, Kiekens RC, Bruijnzeel PL (2005). Skin-infiltrating neutrophils following exposure to solar-simulated radiation could play an important role in photoageing of human skin. Br J Dermatol 152:321–328. Rochette PJ, Therrien JP, Drouin R, Perdiz D, Bastien N, Drobetsky EA, Sage E (2003). UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine-thymine dipyrimidines and correlate with the mutation spectrum in rodent cells. Nucleic Acids Res 31:2786–2794. Romero-Graillet C, Aberdam E, Clement M, Ortonne JP, Ballotti R (1997). Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. J Clin Invest 99:635–642. Rondanelli M, Trotti R, Opizzi A, Solerte SB (2007). Relationship among nutritional status, pro/antioxidant balance and cognitive performance in a group of freeliving healthy elderly. Minerva Med 1998:639–645. Sawane M, Kajiya K (2012). Ultraviolet light-induced changes of lymphatic and blood vasculature in skin and their molecular mechanisms. Exp Dermatol 21 (Suppl 1):22–25. Setlow RB, Carrier WL (1966). Pyrimidine dimers in ultraviolet-irradiated DNA’s. J Mol Biol 17:237–254. Silveira JP, Seito LN, Eberlin S, Dieamant GC, Nogueira C, Pereda MC, Di Stasi LC (2013). Photoprotective and antioxidant effects of rhubarb: inhibitory action on tyrosinase and tyrosine kinase activities and TNF-alpha, IL-1 alpha and alpha-MSH production in human melanocytes. BMC Complement Altern Med 13:49. Situm M, Buljan M, Cavka V, Bulat V, Krolo I, Mihic LL (2010). Skin changes in the elderly people – how strong is the influence of the UV radiation on skin aging? Coll Antropol 34 (Suppl 2):9–13. Sivapirabu G, Yiasemides E, Halliday GM, Park J, Damian DL (2009). Topical nicotinamide modulates cellular energy metabolism and provides broadspectrum protection against ultraviolet radiation-induced immunosuppression in humans. Br J Dermatol 161:1357–1364. Staal A, Van Wijnen AJ, Desai RK, Pols HA, Birkenhager JC, Deluca HF, et al. (1996). Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elements. Endocrinology 137:2001–2011. Stary A, Sarasin A (2000). Ultraviolet A- and singlet oxygen-induced mutation spectra. Methods Enzymol 319:153–165. Stuehr DJ, Kwon NS, Nathan CF (1990). FAD and GSH participate in macrophage synthesis of nitric oxide. Biochem Biophys Res Commun 168: 558–565. Stuehr DJ, Kwon NS, Nathan CF, Griffith OW, Feldman PL, Wiseman J (1991). N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J Biol Chem 266:6259–6263. Surjana D, Halliday GM, Damian DL (2013). Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin. Carcinogenesis 34:1144–1149. Suschek CV, Krischel V, Bruch-Gerharz D, Berendji D, Krutmann J, Kroncke KD, Kolb-Bachofen V (1999). Nitric oxide fully protects against UVA-induced apoptosis in tight correlation with Bcl-2 up-regulation. J Biol Chem 274:6130–6137. Suschek CV, Briviba K, Bruch-Gerharz D, Sies H, Kroncke KD, Kolb-Bachofen V (2001). Even after UVA-exposure will nitric oxide protect cells from reactive oxygen intermediate-mediated apoptosis and necrosis. Cell Death Differ 8:515–527. Suschek CV, Schroeder P, Aust O, Sies H, Mahotka C, Horstjann M, et al. (2003). The presence of nitrite during UVA irradiation protects from apoptosis. FASEB J 17:2342–2344. Takeuchi A, Reddy GS, Kobayashi T, Okano T, Park J, Sharma S (1998). Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects. J Immunol 160:209–218. Thomasset M (1994). Vitamin D and the immune system. Pathol Biol (Paris) 1942:163–172. Towers TL, Freedman LP (1998). Granulocyte-macrophage colony-stimulating factor gene transcription is directly repressed by the vitamin D3 receptor. Implications for allosteric influences on nuclear receptor structure and function by a DNA element. J Biol Chem 273:10338–10348. Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC, Zylicz Z (2003). Itch: scratching more than the surface. QJM 96:7–26. Vanoirbeek E, Eelen G, Verlinden L, Carmeliet G, Mathieu C, Bouillon R (2014). PDLIM2 expression is driven by vitamin D and is involved in the pro-adhesion, and anti-migration and -invasion activity of vitamin D. Oncogene 33:1904–1911. Vile GF, Tanew-Ilitschew A, Tyrrell RM (1995). Activation of NF-kappa B in human skin fibroblasts by the oxidative stress generated by UVA radiation. Photochem Photobiol 62:463–468.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

438 European Journal of Cancer Prevention 2015, Vol 24 No 5

Walther E, Boer I, Piazena H, Bomski B, Klinker L (1989). Initial results of studies of the effect of solar UV irradiation on the curative effect of psoriasis vulgaris in Heiligendamm. Dermatol Monatsschr 175:548–554. Wang J, Lofgren S, Dong X, Galichanin K, Soderberg PG (2011). Dose-response relationship for alpha-tocopherol prevention of ultraviolet radiation induced cataract in rat. Exp Eye Res 93:91–97. Wang SQ, Setlow R, Berwick M, Polsky D, Marghoob AA, Kopf AW, Bart RS (2001). Ultraviolet A and melanoma: a review. J Am Acad Dermatol 44:837–846. Wei H, Zhang X, Wang Y, Lebwohl M (2002). Inhibition of ultraviolet light-induced oxidative events in the skin and internal organs of hairless mice by isoflavone genistein. Cancer Lett 185:21–29. Westermarck J, Hakkinen L, Fiers W, Kahari VM (1995). TNF-R55-specific form of human tumor necrosis factor-alpha induces collagenase gene expression by human skin fibroblasts. J Invest Dermatol 105:197–202.

Wolfle U, Esser PR, Simon-Haarhaus B, Martin SF, Lademann J, Schempp CM (2011). UVB-induced DNA damage, generation of reactive oxygen species, and inflammation are effectively attenuated by the flavonoid luteolin in vitro and in vivo. Free Radic Biol Med 50:1081–1093. Yiasemides E, Sivapirabu G, Halliday GM, Park J, Damian DL (2009). Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis 30:101–105. Zembowicz A, Swierkosz TA, Southan GJ, Hecker M, Vane JR (1992). Potentiation of the vasorelaxant activity of nitric oxide by hydroxyguanidine: implications for the nature of endothelium-derived relaxing factor. Br J Pharmacol 107:1001–1007. Zhang Y, Song S, Fong CC, Tsang CH, Yang Z, Yang M (2003). cDNA microarray analysis of gene expression profiles in human fibroblast cells irradiated with red light. J Invest Dermatol 120:849–857.

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Solar ultraviolet radiation from cancer induction to cancer prevention: solar ultraviolet radiation and cell biology.

Although decades have elapsed, researchers still debate the benefits and hazards of solar ultraviolet radiation (UVR) exposure. On the one hand, human...
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