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Review Article
Ultraviolet Radiation‑induced Carcinogenesis: Mechanisms and
Experimental Models
Karthikeyan Ramasamy, Mohana Shanmugam, Agilan Balupillai, Kanimozhi Govindhasamy, Srithar Gunaseelan,
Ganesan Muthusamy, Beualah Mary Robert, Rajendra Prasad Nagarajan

From the Department Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been

Abstract
of Biochemistry and implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits
Biotechnology, Faculty numerous cellular and molecular events which include the generation of inflammatory mediators,
of Science, Annamalai DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling
University, Annamalai Nagar, pathways. UVR‑initiated signal transduction pathways are believed to be responsible for tumor
Tamil Nadu, India 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.
Received: January, 2017.
Accepted: January, 2017. Key Words: DNA damage, experimental models, skin cancer, ultraviolet radiation

Introduction
R adiation 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
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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
Address for correspondence:
Dr. Rajendra Prasad Nagarajan, E‑mail: drprasadnr@gmail.com
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak,
and build upon the work non‑commercially, as long as the author is credited and the new
creations are licensed under the identical terms.

Website: www.journalrcr.org For reprints contact: reprints@medknow.com

How to cite this article: Ramasamy K, Shanmugam M, Balupillai A,

Govindhasamy K, Gunaseelan S, Muthusamy G, et al. Ultraviolet
DOI: 10.4103/0973-0168.199301 radiation-induced carcinogenesis: Mechanisms and experimental
models. J Radiat Cancer Res 2017;8:4-19.

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis

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].
Direct DNA Damages through Formation
of Cyclobutane Pyrimidine Dimers and
Photoproducts
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]
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

Table 1: Characteristics of different wavebands of UV radiations

Properties Waveband
UVA UVB UVC
Wavelength 320-400 nm 285-320 nm 200-285 nm

Strospheric ozone absorption No absorption Partial Complete

Mutagenicity Moderate Strong Very Strong

Cellular chromophore Cytochromes, porphyrines, flavins, DNA DNA

amino acids etc.
DNA damage Indirect singlet oxygen mediated Dierect DNA damage via formation Dierect DNA damage via
oxidative DNA damage (8-deoxy of CPDs and 6-4 photoproducts formation of CPDs and 6-4
guanosine) photoproducts
Skin penetration Deeper skin peneratration; Poor skin penetration; reaches Poor skin penetration; reaches
reaches via epidermis, dermis to mainly epidermis and partly dermis mainly epidermis.
subcutaneous tissues layers of human skin
Target cells Dermal fibroblasts, epidermal Epidrmal Keratinocytes and Epidrmal Keratinocytes and
keratinocytes and melanocytes melanocytes melanocytes
Adverse effects Photoaging Melanoma and nonmelanoma (SCC)Melanoma and nonmelanoma
Inflammation (SCC)
Erythema
Immunosuppression

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis

Figure 1: Ultraviolet B radiation‑induced cyclobutane pyrimidine dimers and 6‑4 photoproducts

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
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 Figure 2: The nucleotide excision repair mechanism
chromophore does not return to the electronic ground state
by mechanisms of energy dissipation such as heat generation
energy incident on the skin is largely from the UVA region
or photon emission but instead initiates chemical reactions
compared to UVB content.
leading to the formation of reactive intermediates and toxic
PPs. Lifetime of the excited state of the chromophore is
Nucleotide Excision Repair Mechanism
sufficiently long to allow interaction with target molecules.
Therefore, it becomes apparent that the physical nature of The most important DNA damage repair system involved
the UVA photons and the chemical nature of the absorbing in excision of damages caused by UVR (such as CPDs
chromophore in the skin determine the ROS generation in the and 6‑4PPs) is the nucleotide excision repair  (NER)
human skin.[19] mechanism [Figure  2]. Defective NER resulted in the
development of squamous cell carcinoma (SCC).[22] This
This UVA‑induced ROS, in turn, acts as a powerful system can act in two subpathways: faster transcription‑coupled
mutagen that may cause oxidative DNA damage.[20] repair that operates on transcribed strand of active genes, and
A number of oxidation products of purine bases such slower global genome repair  (GG‑NER)[23,24] that removes
as 8‑oxo‑7,8‑dihydroguanyl  (8‑oxoGua), 8‑oxo‑Ade, lesions within the entire genome. Two‑step recognition model
2,6‑diamino‑4‑hydroxy‑5‑formamidoguanine  (FapyGua), for NER initiation demonstrated that XPC first binds to small
FapyAde, and oxazolone have been reported to form upon ssDNA gap caused by disrupted base pairing.[25] Although
exposure of DNA to UVA radiation.[21] Most of the solar UV XPC is the main initiator of GG‑NER, UVR‑induced CPDs

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis

are a poor substrate for XPC, mainly because they only mildly these patients have more than 1000‑fold increased incidents of
destabilize the DNA helix. Hence, to enhance CPD repair, skin cancers in comparison to general population.[34] Patients
the UVR–DNA damage‑binding protein  (DDB) complex, affected by this syndrome develop skin cancers mostly in
which comprises DDB1  (also known as XPE‑binding sun‑exposed areas.[35‑37] A novel mutation in the XPA gene
factor) and the GG‑NER‑specific protein DDB2, directly results in two truncated protein variants and leads to a severe
binds to UVR‑induced lesions and functions as an auxiliary XP/neurological symptoms phenotype.[38]
damage‑recognition factor by stimulating the subsequent
binding of XPC.[26] XPC binding to the lesions will provide a Chronic Ultraviolet Radiation Exposure
substrate for the association of the transcription initiation factor Induces Carcinogenesis
IIH  (TFIIH) complex, which is a transcription initiation.[27]
It is well established that UVR is involved in all three stages of
TFIIH was originally identified as an essential TF, but it can
carcinogenesis.[39] UVR radiation acts as both tumor initiator and
switch between functions in transcription and in NER. It has
tumor promoter in several animal models.[40] The development
two helicase subunits, namely, XPB  (encoded by ERCC3)
of UVR‑mediated skin cancer is a complex multistage process
and XPD (encoded by ERCC2), has opposite polarities and
including a three‑step initiation‑promotion‑progression system
extends the open DNA configuration around the lesion, and
mediated through various cellular, biochemical, and molecular
verifies the presence of a lesion. The ATPase activity of XPB
changes.[41] Initiation is the irreversible process, by which
is mainly responsible for recruiting TFIIH to site of DNA
normal keratinocytes acquire (through somatic mutations)
damage, and the 5ʹ–3ʹ unwinding activity of XPD seems to be
the irreversible capacity to form tumors.[42] Promotion is a
indispensable for NER.[28] Studies using in vitro experimental
largely reversible process during which a clone of initiated
system clearly demonstrated that the XPD helicase is mainly
keratinocytes expands to form a papilloma.[43] During the
required for damage verification. If the XPD helicase failed
process of tumor progression, a series of genetic and epigenetic
to detect any damage, the repair reaction may be aborted.[29]
events transforms the premalignant papilloma into a malignant
Damage verification also probably involves the XPA protein,
SCC. These genetic alterations mainly occur in proto‑oncogenes
which detects nucleotides with altered chemical structures
and tumor suppressor genes, these eventually make the cells
in ssDNA.[30] After a lesion detection and verification,
become resistant to signals for terminal differentiation. Chronic
they must be excised, such this reaction is catalyzed by
UV exposure induces clones of cells overexpressing mutant
the structure‑specific endonucleases XPF–ERCC1 and
p53 in the interfollicular epidermis and subsequently SCCs
XPG (encoded by ERCC5), which incise the damaged strand
with similar p53 mutations. Mutated p53 may give cells growth
at short distances 5ʹ and 3ʹ from the lesion.[31] Coordination of
advantage over neighboring cells by impaired apoptosis.[44]
incision involves the assembly of XPA, XPG, and replication
Ambothi et  al.  (2015)  reported mutated p53 expression in
protein A  (RPA) at NER lesions that are marked by XPC and
the tumor of chronic irradiated mouse skin.[45] UVR‑induced
verified by TFIIH. XPA almost interacts with all NER proteins;
skin tumors progress from foci of epithelial hyperplasia to
hence, it is considered to be a central coordinator of the NER
papillomas and ultimately into squamous cell and spindle
complex.[32] XPA diverse function includes stimulating lesion
cell carcinomas.[40,46] Gunaseelan et  al. demonstrated chronic
verification by TFIIH26 and binding to altered nucleotides
UVB‑mediated proliferative markers expression and subsequent
in ssDNA. RPA, a single‑strand binding protein, protects
skin carcinogenesis in experimental animals.[47]
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
Ultraviolet Radiation‑mediated Signal
recruited by TFIIH, is essential to enable XPF–ERCC1 to Transduction Events
make the 5ʹ incision, which is sufficient to initiate gap‑filling UVR exposure induces DNA damage, photoaging, and
DNA synthesis even before the XPG‑mediated 3ʹ incision malignant transformation in the skin. UVR activates signaling
is made.[32] DNA gap‑filling synthesis and ligation are cascades that promote the survival of potentially malignant
executed by the replication proteins proliferating cell nuclear cells, resulting in tumor initiation. The UVR‑induced stress
antigen  (PCNA), replication factor C, DNA Pol δ, DNA response in the skin is multifaceted and involves coordinated
Pol ε, or DNA Pol κ, and DNA ligase 1 or XRCC1–DNA activation of numerous pathways controlling DNA damage
ligase 3, which specific proteins are involved depends on the repair, inflammation, and kinase‑mediated signal transduction
proliferative status of the cell. DNA Pol ε‑dependent repair that lead to either cell survival or cell death.[48]
and subsequent ligation by DNA ligase 1 mainly occur in
UVA‑mediated ROS generation appears to be critical for
replicating cells, whereas DNA Pol δ and DNA Pol κ are
the activation of signal transduction cascades such as
the main NER polymerases in nonreplicating cells, in which
mitogen‑activated protein kinases  (MAPKs)  (p38, ERK, and
nucleotide pool concentrations are low.[33] The expression of
Jun N‑terminal kinase [JNK]).[49] In fibroblasts, UVA‑activated
DNA ligase 1 is also low in noncycling cells, and under these
p38 and JNK have been reported with the formation of
circumstances, the constitutively present XRCC1–DNA ligase
photosensitized singlet oxygen.[50] These MAPK subfamily
3 complex seals the gap [Figure 2].
members activated in response to UVR potentially contribute
The pivotal role of NER in preventing cells from damages to cell survival. It is well known that ROS generation during
induced by UVR has been well exemplified in patients with the the UVR exposure in human keratinocytes activates estimated
autosomal recessive condition xeroderma pigmentosum (XP); glomerular filtration rate/ERK1/2 and p38 signaling pathways.[51]

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis
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/m2) 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/cm2) 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/cm2; 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
8 Journal of Radiation and Cancer Research  ¦  Volume 8  ¦  Issue 1  ¦  January-March 2017
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
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.
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]
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Table 2: Mechanisms and experimental models involved in UV-mediated cancer and photo aging
UV radiation Experimental model Mechanism studied Reference
Human dermal fibroblasts Lycogen prevented UVA-induced skin aging through Yang et al., 2014.[66]
targeting NF-κB translocation.
Human melanoma cell line AVS073, a polyherbal formula, prevented UVA-induced Panich et al., 2013.[67]
melanogenesis through a redox mechanism involving
glutathione-related antioxidant defenses.
Melanoma cell lines (Mel-RM, Sk- Investigated the role of NER in UVA-induced Murray et al., 2016.[68]
Mel-28, MM200, and Me4405) melanomagenesis.
Lymphoblastoid cell lines (GM005, Studied UVA induced irreparable transcription-blocking Brem et al., 2009.[69]
AG7075 and GM2345) DNA lesions.
Human keratinocytes cell line Identified potentially cytotoxic lesions induced by UVA Reelfs et al., 2011.[70]
(HaCaT). photoactivation of DNA 4-thiothymidine.
Studied UVA-induced DNA double-strand breaks and Greinert et al., 2012.[71]
repair of clustered oxidative DNA damages.
UVA Investigated inhibition of MAPKs using selective Silvers et al., 2003.[72]
pharmacologic inhibitors for chemopreventive strategies.
Resveratrol sensitized UVA induced apoptosis in human Boyer et al., 2012.[73]
keratinocytes through mitochondrial oxidative stress and
pore opening.
Studied UVA-induced activation of Ras/ERK/AKT and Zhao et al., 2013.[74]
NF-κB pathways and their role in UV-induced PTEN
downregulation.
Studied IL-6 production in response to UVA-induced Kawano et al., 2015.[75]
ATP release and activation of P2Y11 and P2Y13
receptors.
Human Caucasian dysplastic oral UVA-irradiated dysplastic keratinocytes developed Nechifor et al., 2012.[76]
keratinocytes (DOK). mechanisms leading to cell survival, following a non-
lethal exposure.
Adult human retinal pigment Observed protective effects of resveratrol against UVA- Chan et al., 2015.[77]
epithelial cells (ARPE19). induced damages through suppressing H2O2 production,
MAPK activation, and COX-2 expression.
Primary human epidermal Observed indirect modulation of Nrf2-ARE pathway to Chaiprasongsuk
melanocytes. promote redox balance by photoprotective compounds et al., 2016.[78]
for photooxidative damage and hyperpigmentation.
Adult human retinal pigment Studied protective effect of green tea catechins against Chan et al., 2008.[79]
epithelial cells (ARPE19). oxidation of UVA-induced ocular disorders.
Primary neonatal human Studied melanocytes vulnerability to UVA-mediated Redmond et al., 2014.[80]
keratinocytes bystander oxidative signaling.
Human lens epithelial cell line (SRA Observed thioredoxin reductase activity important than Padgaonkar et al., 2015.[81]
01/04). GSH level for protection against UVA light.
Chinese hamster irs1SF cell line. Studied repair protein hXRCC3 as a target for UVB- Girard et al., 2013.[82]
induced DNA repair mechanism.
UVA Primary human dermal fibroblasts. Studied prevention of UVA-induced oxidative damage Bruge et al., 2014.[83]
using UV filters.
Normal human lung fibroblasts Studied singlet oxygen-mediated oxidation and alterationGraindorge et al., 2015.[84]
MRC5 of dynamic DNA replication.
Human primary fibroblasts (FEK4 Studied mitochondria-targeted iron against solar Reelfs et al., 2016.[85]
and FCP7) ultraviolet-A radiation.
C57BL/6J Mice Studied photoaging and matrix metalloproteinases Sayama et al., 2010.[86]
expression in UVA-irradiated mice skin.
SKH:HR-1 hairless mice Hemeoxygenase induction mediates the Reeve and Tyrrell, 1999[87]
photoimmunoprotective activity of UVA radiation in the
mouse.
UVB Human keratinocyte Studied chronic UVB-irradiation initiated basal Chang et al., 2014.[88]
keratinocytes proliferation and facilitates SCC
development.

Contd...

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis
Table 2: Contd
UV radiation Experimental model
UVB Human fibroblasts cell lines
(HT1080)
Primary human fibroblasts
Mouse keratinocyte cell line (3PC) Identified TC-PTP as a novel potential target for both the Lee et al., 2015.[99]
Human hepatoma cells (HepG2)
Human epidermal melanocyte cell Expression of miRNAs in melanocytes in response to
line (Pig1)
Balb/MK2 keratinocytes
UVB Human epidermal melanocytes
Mouse epithelial cell line JB6’
Mouse 308 keratinocyte cell line
JB6 P+ mouse epidermal C141 cells Studied quercitrin as an antioxidant against UVB
Human blood lymphocytes
Human blood lymphocytes
10 Journal of Radiation and Cancer Research  ¦  Volume 8  ¦  Issue 1  ¦  January-March 2017
Mechanism studied Reference
Investigated the role of p21 in apoptosis, proliferation, Chen et al., 2015.[89]
cell cycle arrest, and antioxidant activity in UVB-
irradiated HaCaT keratinocytes.
Investigated the role of afzelin against UVB-induced Shin et al., 2013.[90]
photoaging and development of skin cancer through
modulation of CPDs formation.
Studied the effect of quantum dots on ROS response in Mortensen et al., 2015.[91]
keratinocytes during UVB irradiation.
Studied IL-15 exxpression in response to UVB- Blauvelt et al., 2015.[92]
Radiation .
Studied UVB-stimulated expression of NF-κB and Terazawa et al., 2015.[93]
attenuation through p38/MSK1/NFκBp65Ser276 axis
using siRNA transfection.
Developed in vitro progression model for UVB-induced Tyagi et al., 2015.[94]
skin
carcinogenesis. Lee et al., 2012.[95]
Studied the role of nitric oxide in UVB-induced Jung et al., 2016.[96]
photoaging effects.
Evaluated naringenin as potent anti-photoaging Jung et al., 2016.[96]
agent by suppressing ERK2 activity and decreasing
FRA1 stability, followed by down-regulation of AP-1
transactivation and MMP-1 expression.
Analyzed β-HPV E6 expression on carcinogenic Wallace et al., 2012.[97]
potential of UVB exposure by studying p300
degradation and ATR levels, thymine dimer persistence
and UVB induced DSBs.
Studied mechanisms DNA damage and DNA processing Ortolan and Menck, 2013.[98]
machinery in the genome of UVB-irradiated cells.
prevention and treatment of UVB-induced human skin
cancer.
Demonstrated TRIM29 to enter a protective alternative Bertrand-Vallery et al., 2010.
differentiation process after UVB stress. [100]
Jian et al., 2014.[101]
UVB irradiation and demonstrated a functional role
for miR-340 in the regulation of dendrite formation and
melanosome transport in melanocytes
lincRNA-p21 function as a tumor suppressor gene in Hall et al., 2015.[102]
UVB-induced non-melanoma skin cancer where the loss
of lincRNA-p21 expression results in the evasion of
apoptosis.
Demonstrated UVB-stimulated TNFα release p38 Muthusamy and Piva, 2013.
MAPK signaling. [53]
Silibinin against ultraviolet-B radiation-induced DNA- Narayanapillai et al.,
damage and apoptosis by enhancing interleukin-12 2014.[103]
expression in JB6 cells and SKH-1 hairless mouse
skin.
Studied UVB induced β-catenin signaling in Smith et al., 2012.[104]
keratinocytes.
Yin et al., 2013.[105]
irradiation-induced oxidative damage to skin.
Demonstrated photoprotective effect of sesamol on Prasad et al., 2005.[106]
UVB-radiation induced oxidative stress in human
blood lymphocytes
Studied caffeic acid against UVB induced oxidative Prasad et al., 2009.[107]
damage in human blood lymphocytes.
Contd...
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Ramasamy, et al.: Mechanisms of UVR carcinogenesis
Table 2: Contd
UV radiation Experimental model
Human dermal fibroblasts adult
(HDFA)
Human dermal fibroblasts adult
(HDFA)
3D organotypic skin-melanoma
spheroid model (SBCL2 (RGP),
WM-115 (VGP) and 451-LU (MM)) malignant melanoma and for the investigation of
3D human skin equivalent system
(HDFA cells)
3D reconstituted normal human skin Studied protective effect of tropical highland
equivalent model
SKH-1 mice
HR-1 hairless mice
UVB C57BL/6 mice
C3H/HeN mice
Nrf2 KO and WT C57BL/6 mice
CD1d-knockout (CD1d−/−) mice
HR-1 hairless mice
Swiss albino mice
Journal of Radiation and Cancer Research  ¦  Volume 8  ¦  Issue 1  ¦  January-March 2017
Mechanism studied Reference
Observed sesamol as photoprotective agent against Ramachandran et al., 2010.
UVB-induced apoptotic and inflammatory signaling. [108]
Studied 7-Hydroxycoumarin against UVB-induced Karthikeyan et al., 2016.[109]
activation of NF-κB and subsequent overexpression of
matrix metalloproteinases and inflammatory markers.
Developed organotypic human skin-melanoma Vörsmann et al., 2013.[110]
model to facilitate therapeutic outcomes for
cytotoxic treatments and tailored therapies in a more
physiological setting.
Studied photoprotection using almond phytochemicals Evans-Johnson
and α-Tocopherol. et al.,2015.[111]
Calvo-Castro et al.,2013.[112]
blackberry juice against UVB-mediated damages in a
reconstituted skin equivalent model
Investigated quercitrin against UVB irradiation- Yin et al., 2013.[105]
induced oxidative damage to animal skin.
Studied silibinin against UVB radiation-induced DNA- Narayanapillai
damage and apoptosis by enhancing interleukin-12 et al., 2014.[103]
expression in JB6 cells and SKH-1 hairless mouse
skin.
Demonstrated docosahexaenoic acid against UVB- Rahman et al.,2011.[113]
induced activation of NF-kB and expression of COX-2
and NOX-4 in HR-1 hairless mouse skin by blocking
MSK1 signaling.
Demonstrated baicalin against UVB irradiation induced Zhang et al., 2014.[114]
photoaging.
Observed silymarin for ultraviolet radiation-induced Vaid et al., 2013.[115]
immune suppression through DNA repair-dependent
activation of dendritic cells and stimulation of effector
T cells.
Illustrated Nrf2 null enhances UVB-induced skin Saw et al., 2014.[116]
inflammation and extracellular matrix damages.
Observed UVB-induced skin inflammation and Ryser et al., 2014.[117]
cutaneous tissue injury on the MHC class I–like protein,
CD1d
Investigated protective effect of indole-3-pyruvate Aoki et al.,2014.[118]
against ultraviolet B-induced damage to cultured HaCaT
keratinocytes and the skin of hairless mice
Studied caffeic acid against UVB-induced inflammation Balupillai et al.,2015.[119]
and photocarcinogenesis through activation of
peroxisome proliferator-activated receptor-gamma in
mouse skin.
Studied ferulic acid agaist UVB-radiation induced Ambothi et al., 2015.[45]
photocarcinogenesis through modulating inflammatory
and apoptotic signaling in Swiss albino mice.
Observed caffeic acid against chronic UVB-induced Agilan et al.,2016. [55]
cellular proliferation through JAK-STAT3 signaling in
mouse skin.
Observed preventive effect of linalool on acute and Gunaseelan et al., 2016.[47]
chronic UVB-mediated skin carcinogenesis in Swiss
albino mice.
Observed modulatory effect of gentisic acid on the Sharma et al., 2004.[120]
augmentation of biochemical events of tumor promotion
stage by benzoyl peroxide and ultraviolet radiation in
Swiss albino mice.
Contd...
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Ramasamy, et al.: Mechanisms of UVR carcinogenesis

Table 2: Contd
UV radiation Experimental model Mechanism studied Reference
K14 HPV-8/K14 N17Rac1 double Observed the deletion of epidermal Rac1 inhibits HPV-8 Deshmukh et al.,2016.[121]
transgenic mice induced skin papilloma formation and facilitates HPV-8-
and UV-light induced skin carcinogenesis.
CAG-AID–Tg mice Observed the involvement of activation-induced cytidine Nonaka et al.,2016.[122]
deaminase in skin cancer development.
Cdk4R24C::Tyr-NRASQ61K mice Studied the activation and migration of melanocytes to Handoko et al.,2015.[123]
the epidermis after neonatal UVR enhances melanoma
development.
Cdk4R24C/ Studied the melanoma susceptibility as a complex trait Ferguson et al.,2015.[124]
R24C::Tyr-NRASQ61K/+ mice and observed geneticvariation controls during all stages
of tumor progression.
UVC Human skin fibroblasts (CRL-1502) Observed dose dependent induction of cell cycle arrest Gentile et al.,2003.[125]
and apoptosis by UVC radiation.
RSa cells Demonstrated HSP27 involvement in the UVC- Wano et al., 2004.[126]
resistance of human cells, possibly via functioning in
nucleotide excision repair.
A-375, SK-MEL-2, SK-MEL-28, Observed activation of p53 in response to UV damages. Haapajarvi et al., 1999.[127]
WM239, G361, and Malme-3M
U2OS, SW480, and HCT116 cells Studied promyelocytic leukemia protein, in conjunction Seker etal., 2003.[128]
with p53 and BLM, contributes to the cellular response
to UVC-induced DNA damage and its repair.
UACC903 and UACC903(+6) Observed apoptosis during UVC irradiation. Zhang et al.,2007.[129]
Human diploid VH10tert foreskin Delayed c-Fos activation in human cells triggers XPF Tomicic et al., 2011.[130]
fibroblast cell line induction and an adaptive response to UVC-induced
DNA damage and cytotoxicity.
MCF-7 Involvement of heat shock protein 27 in the Tong et al.,2012.[131]
susceptibility of KT human breast cancer cells to UVC
and interferon lethality.
NIH 3T3 cells and A431 cells Observed COX-2 role in cellular response to UVC Tai et al., 2012.[132]
irradiation in various cell lines.
SV40-transformed human fibroblastsObserved DNA replication arrest during UVC Rodrigo et al.,2000.[133]
lesions hyperphosphorylation replication protein A in
mammalian cells.
Wild type mouse embryo fibroblasts Studied UVC effect on COX-2 mRNA binding protein László et a1., 2009. [134]
(MEFS/S) and mutated ones TIAR.
(MEFA/A)
Primary human skin fibroblasts Studied UVC-induced mitochondrial degradation via Bess et al.,2013.[135]
autophagy correlated with mtDNA damage removal in
primary human fibroblasts.
Human lymphoblastoid TK6 cell lineSynergistic gene expression signature Glover et al.,2015.[136]
observed in TK6 cells upon co-exposure to
UVC-irradiation and protein kinase C activating
tumor promoters.
Human fibroblast cell line NHF1- Observed cyclobutane pyrimidine dimer density as Sproul et al., 2014.[137]
hTERT a predictive biomarker of the biological effects of
ultraviolet radiation in normal human fibroblasts.
Human osteoblast-like cells(MG-63) Observed the effects of different wavelengths of UV on Gao et al., 2013.[138]
photofunctionalization.
UVC CB-17 severe combined immune Observed UVC on human platelets characterization in Zhi et al., 2013.[139]
deficient (SCID) mice mouse model.
Transgenic mice Observed spectrum of UVC-induced mutation in mouse Ikehata et al., 2015.[140]
skin epidermis.

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Ramasamy, et al.: Mechanisms of UVR carcinogenesis
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
Journal of Radiation and Cancer Research  ¦  Volume 8  ¦  Issue 1  ¦  January-March 2017
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
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
13
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Ramasamy, et al.: Mechanisms of UVR carcinogenesis
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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Journal of Radiation and Cancer Research  ¦  Volume 8  ¦  Issue 1  ¦  January-March 2017 19