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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 8  |  Issue : 1  |  Page : 4-19

Ultraviolet radiation-induced carcinogenesis: Mechanisms and experimental models


Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India

Date of Web Publication1-Feb-2017

Correspondence Address:
Rajendra Prasad Nagarajan
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-0168.199301

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  Abstract 

Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis.

Keywords: DNA damage, experimental models, skin cancer, ultraviolet radiation


How to cite this article:
Ramasamy K, Shanmugam M, Balupillai A, Govindhasamy K, Gunaseelan S, Muthusamy G, Robert BM, Nagarajan RP. Ultraviolet radiation-induced carcinogenesis: Mechanisms and experimental models. J Radiat Cancer Res 2017;8:4-19

How to cite this URL:
Ramasamy K, Shanmugam M, Balupillai A, Govindhasamy K, Gunaseelan S, Muthusamy G, Robert BM, Nagarajan RP. Ultraviolet radiation-induced carcinogenesis: Mechanisms and experimental models. J Radiat Cancer Res [serial online] 2017 [cited 2017 May 23];8:4-19. Available from: http://www.journalrcr.org/text.asp?2017/8/1/4/199301


  Introduction Top


Radiation is classified as nonionizing radiation (NIR) and ionizing radiation (IR). IRs possess shorter wavelengths with higher frequencies and higher energy, whereas NIRs encompass long wavelength (>100 nm) with low photon energy (<12.4 eV). Except for the narrow visible region, NIR cannot be perceived by any of the human senses unless its intensity is so great that it is felt as heat. The NIR spectrum is divided into two main regions, optical radiations and electromagnetic fields. The optical radiations can be further subdivided into ultraviolet (UV), visible, and infrared radiations. The electromagnetic fields are further divided into radiofrequency (microwave, very high frequency and low frequency radio wave).[1]

UV radiation (UVR) is classified into near, medium, and far UV according to energy, where near and medium UV is technically nonionizing, but where all UV wavelengths can cause photochemical reactions that to some extent mimic ionization (including DNA damage and carcinogenesis). UVR above 10 eV (wavelength shorter than 125 nm) is considered ionizing. However, the rest of the UV spectrum from 3.1 eV (400 nm) to 10 eV, although technically nonionizing, can produce photochemical reactions that are damaging to molecules by means other than simple heat. Since these reactions are often very similar to those caused by IR, often the entire UV spectrum is considered to be equivalent to ionization radiation in its interaction with many systems (including biological systems).[1] UV rays have more energy than visible light but not as much as X-rays.[2]

The main source of UVR is the sun although it can also come from man-made sources such as tanning beds and welding torches. UVR is considered to be important due to their impact on living organisms. Particularly, exposure to UVR causes severe health effects in human beings that include skin diseases, immunosuppression, photoaging, cataract, and skin cancer.[3] This review mainly explains the mechanisms of UVR-induced carcinogenesis and experimental models employed in the study of UV-related cellular and molecular changes.

Based on the wavelength, UVR is categorized into three types such as ultraviolet C (UVC; 200–280 nm), ultraviolet B (UVB; 280–320 nm), and ultraviolet A (UVA; 320–400 nm). The UVC spectrum is highly mutagenic but does not reach the earth's surface because it is completely absorbed by the stratospheric ozone layer. Conversely, UVA and UVB wavelengths represent 95% and 5% of the UV spectrum reaching the earth's surface, respectively, with UVA penetrating the atmospheric and stratospheric ozone, while UVB radiation is predominantly absorbed by these layers. UVB is considerably 20-fold less abundant than UVA; its energy is more efficiently absorbed by cellular molecules leading to damages within cells and tissues at significantly lower doses than UVA. Since nucleic acids are one among the primary chromophores, UVB causes direct DNA damage resulting in the formation of bulky damages between adjacent pyrimidine sites.[4] UVB can also generate reactive oxygen species (ROS), but mechanism of their generation is different from that of UVA irradiation. UVA is generally considered to be less carcinogenic than UVB.[5] Low-energy UVA radiation is weakly absorbed by DNA but can be absorbed by other cellular chromophores and induces mainly oxidative changes through generating of ROS leading indirectly contribute to the DNA damage [Table 1].
Table 1: Characteristics of different wavebands of UV radiations

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  Direct DNA Damages Through Formation of Cyclobutane Pyrimidine Dimers and Photoproducts Top


Absorption of UV rays by DNA generates the formation of mutagenic cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [Figure 1]. These damages are the major cause of skin cancer because, in turn, they can lead to signature UV mutations.[6] A four-member ring structure involving C5 and C6 of both neighboring bases referred to as CPDs is formed in higher quantity by cycloaddition reaction between two pyrimidine bases in single-stranded DNA (ssDNA) and at the flexible ends of poly (dA)-(dT) tracts but not at their rigid center. Horikoshi et al. illustrated the crystal structure of the nucleosome containing UVB-induced CPDs.[7] Cannistraro et al. have shown that CPDs of TCG sites deaminate and could contribute to the formation of UV mutation hotspots.[8] Song et al. showed rotational position and flanking sequence in a nucleosome which modulate CPD formation and subsequent deamination contribute to C to T mutations which are associated with skin cancer induction.[9]
Figure 1: Ultraviolet B radiation-induced cyclobutane pyrimidine dimers and 6-4 photoproducts

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The 6-4PPs are formed by a noncyclic bond between C6 (of the 5′-end) and C4 (of the 3′-end) of the involved pyrimidines through spontaneous rearrangement of the oxetane (when the 3′-end is thymine) or azetidine (when the 3′-end is cytosine) intermediates.[10] The 6-4PPs are converted into their Dewar valence isomers upon exposure to UVB radiation that may further undergo reversion to the 6-4PPs upon exposure to short-wavelength UVR.

UVB-induced ROS as well as DNA lesions such as CPDs and 6-4PPs may cause primary as well as secondary breaks. These lesions are commonly associated with transcription/replication blockage that may lead to production of DNA double-strand breaks (DSBs) at the sites of collapsed replication forks of CPDs-containing DNA.[11],[12] The generation of DNA DSBs in UVR-irradiated cells, specifically in replicating DNA, has been known for a long time, and DNA strand breaks are observed extensively.[13] It was assumed that initial PPs are converted into DSBs during DNA replication due to “collapse of replication forks.”[14] Overall, it seems that UVR does not directly produce DSBs but rather produces pyrimidine dimers and other PPs leading to replication arrest and DSBs.[11] It has been considered that UV-induced DNA lesions such as CPDs, 6-4PPs, abasic site, strand breaks, and oxidative product are the predominant and most persistent lesions and if not repaired may cause severe structural distortions in the DNA molecule, thereby affecting the important cellular processes such as DNA replication and transcription, compromising cellular viability and functional integrity, and ultimately leading to mutagenesis, tumorigenesis, and cell death.[15]


  Indirect DNA Damages Through Formation of Reactive Oxygen Species Top


Indirect mechanisms of UVR-mediated DNA damage are observed at longer wavelengths (UVA, visible light), at which DNA absorbs only weakly or not at all. An increasing body of experimental evidence supports a causative role of UVA irradiation in photoaging and carcinogenesis of human skin by photooxidative mechanisms mediated ROS.[16] The formation of ROS as mediators of photooxidative stress in UV-irradiated skin seems to be dependent on endogenous photosensitizers such as porphyrins, cytochromes, and flavins.[17] The molecular consequences downstream of UVA-driven ROS production on skin structural integrity, signal transduction, gene expression, and ultimately tumorigenic initiation and progression are widely studied, but the upstream molecular mechanisms linking UV-photon absorption with ROS production in the skin have been elusive. According to the first law of photochemistry (Grotthus–Draper law), light must be absorbed by an atom or molecule to initiate a physical or chemical process.[18] Photosensitization occurs when a photoexcited chromophore does not return to the electronic ground state by mechanisms of energy dissipation such as heat generation or photon emission but instead initiates chemical reactions leading to the formation of reactive intermediates and toxic PPs. Lifetime of the excited state of the chromophore is sufficiently long to allow interaction with target molecules. Therefore, it becomes apparent that the physical nature of the UVA photons and the chemical nature of the absorbing chromophore in the skin determine the ROS generation in the human skin.[19]

This UVA-induced ROS, in turn, acts as a powerful mutagen that may cause oxidative DNA damage.[20] A number of oxidation products of purine bases such as 8-oxo-7,8-dihydroguanyl (8-oxoGua), 8-oxo-Ade, 2,6-diamino-4-hydroxy-5-formamidoguanine (FapyGua), FapyAde, and oxazolone have been reported to form upon exposure of DNA to UVA radiation.[21] Most of the solar UV energy incident on the skin is largely from the UVA region compared to UVB content.


  Nucleotide Excision Repair Mechanism Top


The most important DNA damage repair system involved in excision of damages caused by UVR (such as CPDs and 6-4PPs) is the nucleotide excision repair (NER) mechanism [Figure 2]. Defective NER resulted in the development of squamous cell carcinoma (SCC).[22] This system can act in two subpathways: faster transcription-coupled repair that operates on transcribed strand of active genes, and slower global genome repair (GG-NER)[23],[24] that removes lesions within the entire genome. Two-step recognition model for NER initiation demonstrated that XPC first binds to small ssDNA gap caused by disrupted base pairing.[25] Although XPC is the main initiator of GG-NER, UVR-induced CPDs are a poor substrate for XPC, mainly because they only mildly destabilize the DNA helix. Hence, to enhance CPD repair, the UVR–DNA damage-binding protein (DDB) complex, which comprises DDB1 (also known as XPE-binding factor) and the GG-NER-specific protein DDB2, directly binds to UVR-induced lesions and functions as an auxiliary damage-recognition factor by stimulating the subsequent binding of XPC.[26] XPC binding to the lesions will provide a substrate for the association of the transcription initiation factor IIH (TFIIH) complex, which is a transcription initiation.[27] TFIIH was originally identified as an essential TF, but it can switch between functions in transcription and in NER. It has two helicase subunits, namely, XPB (encoded by ERCC3) and XPD (encoded by ERCC2), has opposite polarities and extends the open DNA configuration around the lesion, and verifies the presence of a lesion. The ATPase activity of XPB is mainly responsible for recruiting TFIIH to site of DNA damage, and the 5′–3′ unwinding activity of XPD seems to be indispensable for NER.[28] Studies using in vitro experimental system clearly demonstrated that the XPD helicase is mainly required for damage verification. If the XPD helicase failed to detect any damage, the repair reaction may be aborted.[29] Damage verification also probably involves the XPA protein, which detects nucleotides with altered chemical structures in ssDNA.[30] After a lesion detection and verification, they must be excised, such this reaction is catalyzed by the structure-specific endonucleases XPF–ERCC1 and XPG (encoded by ERCC5), which incise the damaged strand at short distances 5′ and 3′ from the lesion.[31] Coordination of incision involves the assembly of XPA, XPG, and replication protein A (RPA) at NER lesions that are marked by XPC and verified by TFIIH. XPA almost interacts with all NER proteins; hence, it is considered to be a central coordinator of the NER complex.[32] XPA diverse function includes stimulating lesion verification by TFIIH26 and binding to altered nucleotides in ssDNA. RPA, a single-strand binding protein, protects undamaged DNA from endonucleases and also does the proper orientation of XPF–ERCC1 and XPG to specifically incise only where the damage occurred/recognized. XPG is recruited by TFIIH, is essential to enable XPF–ERCC1 to make the 5′ incision, which is sufficient to initiate gap-filling DNA synthesis even before the XPG-mediated 3′ incision is made.[32] DNA gap-filling synthesis and ligation are executed by the replication proteins proliferating cell nuclear antigen (PCNA), replication factor C, DNA Pol δ, DNA Pol ε, or DNA Pol κ, and DNA ligase 1 or XRCC1–DNA ligase 3, which specific proteins are involved depends on the proliferative status of the cell. DNA Pol ε-dependent repair and subsequent ligation by DNA ligase 1 mainly occur in replicating cells, whereas DNA Pol δ and DNA Pol κ are the main NER polymerases in nonreplicating cells, in which nucleotide pool concentrations are low.[33] The expression of DNA ligase 1 is also low in noncycling cells, and under these circumstances, the constitutively present XRCC1–DNA ligase 3 complex seals the gap [Figure 2].
Figure 2: The nucleotide excision repair mechanism

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The pivotal role of NER in preventing cells from damages induced by UVR has been well exemplified in patients with the autosomal recessive condition xeroderma pigmentosum (XP); these patients have more than 1000-fold increased incidents of skin cancers in comparison to general population.[34] Patients affected by this syndrome develop skin cancers mostly in sun-exposed areas.[35],[36],[37] A novel mutation in the XPA gene results in two truncated protein variants and leads to a severe XP/neurological symptoms phenotype.[38]


  Chronic Ultraviolet Radiation Exposure Induces Carcinogenesis Top


It is well established that UVR is involved in all three stages of carcinogenesis.[39] UVR radiation acts as both tumor initiator and tumor promoter in several animal models.[40] The development of UVR-mediated skin cancer is a complex multistage process including a three-step initiation-promotion-progression system mediated through various cellular, biochemical, and molecular changes.[41] Initiation is the irreversible process, by which normal keratinocytes acquire (through somatic mutations) the irreversible capacity to form tumors.[42] Promotion is a largely reversible process during which a clone of initiated keratinocytes expands to form a papilloma.[43] During the process of tumor progression, a series of genetic and epigenetic events transforms the premalignant papilloma into a malignant SCC. These genetic alterations mainly occur in proto-oncogenes and tumor suppressor genes, these eventually make the cells become resistant to signals for terminal differentiation. Chronic UV exposure induces clones of cells overexpressing mutant p53 in the interfollicular epidermis and subsequently SCCs with similar p53 mutations. Mutated p53 may give cells growth advantage over neighboring cells by impaired apoptosis.[44] Ambothi et al. (2015) reported mutated p53 expression in the tumor of chronic irradiated mouse skin.[45] UVR-induced skin tumors progress from foci of epithelial hyperplasia to papillomas and ultimately into squamous cell and spindle cell carcinomas.[40],[46] Gunaseelan et al. demonstrated chronic UVB-mediated proliferative markers expression and subsequent skin carcinogenesis in experimental animals.[47]


  Ultraviolet Radiation-Mediated Signal Transduction Events Top


UVR exposure induces DNA damage, photoaging, and malignant transformation in the skin. UVR activates signaling cascades that promote the survival of potentially malignant cells, resulting in tumor initiation. The UVR-induced stress response in the skin is multifaceted and involves coordinated activation of numerous pathways controlling DNA damage repair, inflammation, and kinase-mediated signal transduction that lead to either cell survival or cell death.[48]

UVA-mediated ROS generation appears to be critical for the activation of signal transduction cascades such as mitogen-activated protein kinases (MAPKs) (p38, ERK, and Jun N-terminal kinase [JNK]).[49] In fibroblasts, UVA-activated p38 and JNK have been reported with the formation of photosensitized singlet oxygen.[50] These MAPK subfamily members activated in response to UVR potentially contribute to cell survival. It is well known that ROS generation during the UVR exposure in human keratinocytes activates estimated glomerular filtration rate/ERK1/2 and p38 signaling pathways.[51] Similarly, sublethal doses of UVB potentially activate JNK/SAPK family of MAPK.[52] It has been proved that low-dose UVB irradiation induces rapid and reversible phosphorylation of JNK and p38. Muthusamy and Piva showed that the UVB-stimulated tumor necrosis factor (TNF)-α release from human melanocyte and melanoma cells was mediated by p38 MAPK in human melanocytes.[53] It has also been demonstrated that AP-1 plays a role in the promotion of UVB-induced skin tumors. The use of a dominant-negative c-jun (TAM-67) resulted in 58% reduction in the number of tumors per mouse and a 79% reduction in the size of tumors resulting from UVB (10 kJ/m 2) exposure.[54] UV-mediated tumor promotion and progression could involve angiogenic responses in the epidermis through enhanced expression of AP-1-regulated angiogenic factors. Further such increased vascularity could be required for early development and subsequent malignant tumor development.[39] Cyclooxygenase-2 (COX-2) overexpression and elevated PGE2 levels have been demonstrated in both premalignant skin lesions and skin cancers. UVR directly induces COX-2 in human skin cells, further it activates p38, which is responsible for the stabilization of COX-2 mRNA, leading to increases in protein expression.[39]

In addition, UVR activates a wide range of genes involved in proinflammatory, photoimmunosuppression, and photocarcinogenesis, including interleukin (IL)-1, IL-6, TNF-α, heme oxygenase-1, matrix metalloproteinase-1 (MMP-1), and STAT3; these all favor tumor progression and invasion.[49],[55] Single UVB (180 mJ/cm 2) exposure to the skin of SKH-1 hairless mice resulted in significant upregulation in (i) protein levels of STAT3 and (ii) phosphorylation of STAT3 at tyrosine705. Furthermore, the activation of STAT3 was found to be associated with a decrease in apoptotic response of UVB and a gradual time-dependent increase in hyperplasia.[56] Agilan et al. showed that chronic UVB irradiation (180 mJ/cm 2; thrice weekly for 30 weeks) induces the expression of IL-10 and JAK1 that eventually activates the STAT3 which leads to the transcription of proliferative and antiapoptotic markers such as PCNA, Cyclin-D1, Bcl-2, and Bcl-xl in mouse skin.[55]

Changes in microRNA (miRNA) expression have been shown to be associated with induction and progression of malignant melanoma, the most lethal form of skin cancer.[57],[58] UV irradiation of human primary keratinocytes modulates the expression of several cellular miRNAs. A common set of miRNAs was influenced by exposure to both UVA and UVB. However, each wavelength band also activated a distinct subset of miRNAs. Several investigations indicate that the differentially expressed miRNAs responding to UV have potential functions in the cellular pathways of cell growth and proliferation. It has been reported that the expression of miR-23b, which is a differentiation marker of human keratinocytes, is remarkably upregulated after UVA irradiation.[59] Pothof et al. showed that miRNA-mediated gene silencing modulates the UVC-induced DNA damage response.[60] Guo et al. investigated UVB-regulated miRNAs in the mouse cell line NIH3T3.[61] Dziunycz et al. investigated the expression of miR-21, miR-203, and miR-205 after UVA and UVB irradiation in human keratinocytes.[62] Zhou et al. listed the global miRNA expression changes in human keratinocytes after UVB irradiation.[63] Singh et al. showed UVR-induced TNF-α on the development of cutaneous SCC and differential epidermal expression of miRNAs.[64]


  Experimental Models Employed in Ultraviolet Radiation Carcinogenesis Top


The incidences of skin cancers resulting from chronic UVR exposure are on the increase globally. Hence, the cellular and molecular pathways that are associated with UVR-induced photocarcinogenesis need to be unambiguously elucidated, to develop more robust preventative and treatment strategies against UVR-induced skin cancers.In vitro investigations into the effects of UVR have, to date, mainly involved the use of cell culture and animal models. There were several models employed for the analysis of UVR-induced cellular and molecular changes. These include cellular models such as skin keratinocytes, melanocytes, fibroblasts, and animal models such as hairless SKH-1, Swiss albino mice, and genetically engineered mouse models.[65] [Table 2] illustrates various experimental models employed in UVR-mediated carcinogenesis, inflammation, and oxidative changes.
Table 2: Mechanisms and experimental models involved in UV-.mediated cancer and photo aging

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Hairless mice are valuable for experimental carcinogenesis studies. Carcinogens, promoters, chemopreventive agents, and chemotherapeutic compounds are readily applied to unperturbed hairless skin. Hairless mouse develops multiple independent skin tumors, which may exhibit significant differences in rate of development and aggressiveness. Skin tumors can be induced in hairless mice by chronic exposure to UVR. These unpigmented and immunocompetent mice allow for ready manipulation of the skin, application of topical agents, and exposure to UVR, as well as easy visualization of the cutaneous response.[141] Wound healing, acute photobiologic responses, and skin carcinogenesis have been extensively studied in SKH-1 mice and are well characterized.[142] In addition, tumors induced in these mice resemble, both at the morphologic and molecular levels, UVR-induced skin malignancies in man. Esteve et al. showed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling.[143] Bald et al. studied repetitive UV exposure in a genetically engineered mouse model and observed inflammation and metastatic progression with respect to reactive angiotropism.[144]

The use of a cell culture model has the advantage of providing a controlled environment to study a wide variety of cellular phenomena. Modern tissue culture technology has made it possible to generate human skin equivalents (HSEs) that represent epidermis (keratinocytes), dermis (fibroblasts), and epidermis plus dermis (full-thickness skin) in vitro in relation to UVR-induced skin carcinogenesis including screening of various pharmaceutical compounds. Skin epidermal melanocytes, keratinocytes, and dermal fibroblasts are the widely accepted models for the study of UV-induced changes in gene expression, telomere shortening, and signal transduction pathways.[65]

Solar irradiation effectively reaches through the upper epidermal layers of the skin into the human dermis and dermal capillary system. Up to 50% of UVA can reach the depth of melanocytes and the dermal compartment, but in the case of UVB, only 14% reaches the lower epidermis.[145] It is estimated that photon energy delivered into the lower epidermis and upper dermis is 100 folds higher in the UVA region than in the UVB region. Photooxidative mechanisms of light-driven ROS formation have been demonstrated in cultured human melanocytes. Skin melanocytes from intact murine and human skin are widely accepted as contributors to skin photoaging and carcinogenesis.[146]

Huh et al. employed human keratinocytes for understanding UVB-induced MMP-1 expression.[147] Kim et al. investigated the involvement of hedgehog (Hh) signaling in the photoaging process as well as the use of an Hh-regulating alkaloid compound as a novel therapeutic drug to regulate photoaging in keratinocytes.[148] Boros (2015) investigated microarray analyses to understand the contribution of CPDs during UVB-induced changes of gene expression by transfecting keratinocytes with pseudouridine-modified mRNA (Ψ-mRNA) encoding CPD-photolyase.[149] Robinson and Werth illustrated the role of UV light in the pathogenesis of keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface, and the release of inflammatory cytokines (including interferons, TNF-α, IL-1, IL-6, IL-8, IL-10, and IL-17).[150]

UVR is the major risk factor for causing skin melanoma. Recently, Zhao et al. studied UVR-induced skin cancer in melanocytes, and they found that Sestrin 2 (Sesn2), a member of the evolutionarily conserved stress-inducible protein family Sesn, is upregulated in human melanomas through the p53 and AKT3 pathways.[151] Espinha et al. documented that RhoA, a GTPase inhibition, caused less efficient DNA repair, with elevated levels of DNA lesions such as strand breaks and CPDs, thereby increasing the sensitivity of melanoma cells to UVR effects.[152] Fukumoto et al. studied the involvement of myeloid cell leukemia-1 (Mcl-1 L) in the regulation of UVB-induced apoptosis in melanocytes and found that overexpression of Mcl-1 L noticed possibly by the MEK-ERK-pS-STAT3 pathway, protects melanocytes, and melanoma cells from UVB-induced apoptosis.[153] Cordeiro-Stone et al. studied functional ability intra-S checkpoint during melanoma development by exposing proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines to increasing influences of UVC.[154] It has been found that primary melanocytes displayed reduced UVC-induced inhibition of DNA strand growth and enhanced degradation of p21Waf1 after UVC than fibroblasts. Scott et al. investigated the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes by UVR.[155]

Begovic et al. investigated the mechanism of DNA damage and how cells avoid consequences of damaged DNA in response to UVC exposure in mouse fibroblast – FADD deficient model.[156] Wang et al. studied the role of hyaluronan synthase-2 against environmental stress including UVR-induced apoptosis in skin fibroblasts model.[157] Niu et al. created a photoaging model by irradiating with different doses of UVA in cultured human skin fibroblast cells to study the red lid light interferences in UVA-induced photoaging.[158] They suggested that red light plays a key role in the antiphotoaging of human skin fibroblasts by acting on different signaling transduction pathways. Zeng et al. studied the cellular photoaging in mouse dermal fibroblast cells by exposing repeated subcytotoxic doses of UVB radiation.[159] Karthikeyan et al. studied UVB-induced activation of nuclear factor-κB and subsequent overexpression of MMPs and inflammatory markers in human dermal fibroblast cells.[109]

Reconstructed pigmented human epidermis model, a three-dimensional (3D) HSE, shows morphological and functional characteristics similar to those of in vivo human skin. The reconstructed human skin models are proposed as an additional tool for photoprotection studies.[160],[161] These models possess biological disparities to native skin, which, to some extent, have limited their relevance to the in vivo situation. Fernandez et al. characterized a 3D, tissue-engineered HSE model consisting of primary human keratinocytes cultured on a dermal-derived scaffold as a representation of a more physiologically relevant platform to study keratinocyte responses to UVB radiation.[162] von Neubeck et al. exposed an in vitro 3D human organotypic skin tissue model to low doses of high LET oxygen (O), silicon, and iron ions for studying proliferation and differentiation profiles in the skin tissue and examined the integrity of the skin's barrier function.[163] Park et al. demonstrated that coumestrol, a metabolite of the soybean isoflavone daidzein, has a preventive effect on skin photoaging in 3D HSE model.[164] Qiu et al. demonstrated the skin-depigmenting potential of Paeonia lactiflora root extract using reconstructed pigmented human epidermis.[165] Dos Santos et al. studied in vitro 3D model for studying chronological epidermis aging.[166] Hill et al. described a novel in vitro model for the investigation of early melanoma invasion, such as that which occurs in radial and vertical growth phase melanoma, within a fully humanized cutaneous microenvironment.[167] This model possesses a unique full-thickness 3D skin equivalent (organotypic skin culture) through the incorporation of an inert porous scaffold with appropriate pore sizes to support the 3D growth and cell-cell contact of primary human dermal fibroblasts. Pendaries et al. illustrated knockdown of filaggrin in a 3D reconstructed human epidermis impairs keratinocyte differentiation for UVB-related studies.[168]


  Conclusion Top


Exposure of UVR radiation is associated with a variety of harmful effects to skin cancer. Different wavebands of UVR exhibit different types of cellular and molecular changes. The UVA radiation induces ROS generation through cellular chromophores through photosensitization mechanism which are involved in inflammation and photoaging of the exposed skin. Whereas UVB radiation generates CPDs and 6-4 PPs that mediate mutations in tumor suppressor genes which are involved in the process of tumor initiation in the exposed human skin, both UVA and UVB radiations elicit several signal transduction pathways that result in various carcinogenic events. UVR-mediated carcinogenesis has been well studied in various experimental models. Primary cultures of skin melanocytes, keratinocytes, and dermal fibroblasts served as excellent models for the study of UVA- and UVB-mediated cellular and molecular changes. Further, several 3D cellular models mimicking human skin has recently been developed for the study of UVR-mediated carcinogenesis.

Acknowledgment

The authors greatly acknowledge the Department of Science and Technology (DST), Government of India, New Delhi, for providing financial assistance to Dr. G. Kanimozhi under DST-SERB scheme (File No: SB/YS/LS-90/2013 dated October 04, 2013).

Financial support and sponsorship

The authors greatly acknowledge the Department of Science and Technology (DST), Government of India, New Delhi, for providing financial assistance to Dr. G. Kanimozhi under DST-SERB scheme (File No: SB/YS/LS-90/2013 dated October 04, 2013).

Conflicts of interest

There are no conflicts of interest.

 
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