Monday, September 03, 2007
Solar ultraviolet (UV) radiation is the most important
environmental factor involved in the pathogenesis of skin cancers.
Both UVB (290-320 nm) and UVA (320-400 nm) radiations participate
in cutaneous carcinogenesis. However, the exact role of UVB, UVA,
or interactions between these wavebands (and also visible and
infrared radiations) remains unknown.
Epidemiological and clinical data, in addition to causing
specific UV mutations in skin cancers, clearly demonstrate the role
of UV irradiations in the development of skin carcinomas.
Pyrimidine dimer-induced C:G to T:A and CC:GG to TT:AA mutations
are considered as UV-signature mutations present in squamous and
basal-cell carcinomas and induced by both UVB and UVA
The exact role of UVB and UVA in melanoma pathogenesis is
largely unknown. Using a hybrid fish model, it has been suggested
that UVA may be the main factor of UV-induced melanoma.2
UVB radiation is directly absorbed by DNA and is the most energetic
and mutagenic component of the solar spectrum. In contrast to UVB
radiation, UVA is poorly absorbed by DNA and its genotoxic effects
have been mainly linked to the induction of oxidative stress and,
consequently, oxidative damages of cell components. Different
studies show the mutagenic effects of UVA irradiations in cultured
cells.3 Moreover, UVA induces skin tumors in
mice4 and is involved in
Thus, until recently, the role of UVA in skin carcinogenesis and
other cutaneous pathologies (as photodermatoses or photoaging) has
been associated with reactive oxygen species (ROS). The
8-oxo-7,8-dihydro-2,-deoxyguanosine (8-oxodGuo) represents the most
important DNA photooxidative lesion induced by UVA (in much larger
amounts than strand breaks). However, 8-oxodGuo does not appear to
be correlated with the UVA mutation spectrum, suggesting that other
lesions are involved in UVA mutagenesis.
Other studies show that UVA could induce cyclobutane pyrimidine
dimers (CPDs) in mammalian cells and skin, and even that the yield
of CPDs could be higher than 8-oxodGuo. But in contrast to UVB, UVA
only seemed to induce CPDs at TT sites without any formation of
pyrimidine (6-4) pyrimidone photoproducts, suggesting that the
effects of UVA could imply other mechanisms than a direct
Two recent studies show the role of UVA effects on human skin.
The first, by Agar et al., was done to identify whether
UVA or UVB caused particular gene mutations.6 These
authors used laser capture microdissection and automated sequencing
of the p53 gene to identify mutations caused by UVA or UVB in
potentially human pre-malignant (solar keratosis, SK) and malignant
skin tumors (squamous cell carcinomas, SCC). The number of
mutations caused by UVB and UVA was similar in SCC and not
substantially higher than in benign SK. UVA-induced mutations were
predominantly related to oxidative lesions and few CPDs and C-T
transitions were found. Interestingly, there was a 77% increase in
the number of ROS-induced mutations in SCC compared to SK,
suggesting that reactive oxygen may drive progression of SK to SCC
through increased mutations. Moreover, UVA-induced mutations were
more prevalent in the lower areas of tumors, whereas UVB-induced
mutations were largely limited in the upper layers of tumors. This
could be linked to the fact that UVA wavelengths penetrate deeper
in skin than shorter UVB wavelengths. These data, showing a
predominant role of ROS in UV-induced mutations and the presence of
UVA-induced mutations at a greater depth than UVB, confirm the
importance of UVA radiation in skin carcinogenesis.
The second study, by Mouret et al., determined the
yield of formation of different DNA lesions using the HPLC
(high-performance liquid chromatography) analytical method
associated with tandem mass spectrophotometry detection (for
bipyrimidine photoproducts) or electrochemical detection for
8-oxodGuo, within whole human skin (from breast plastic surgery)
exposed to UVA radiation.7 UVA radiation of whole skin
induced CPDs mainly at TT sites in larger amounts than 8-oxodGuo
(9-fold higher frequency). Moreover, TT lesions remained present 48
hours after the end of irradiations and were significantly higher
for UVA (72% at 48 hours) compared to UVB (55% at 48 hours). These
data of low repair rates are in agreement with previous studies.
The authors also determined the protection provided by the skin
against formation of DNA lesions by either UVB or UVA. Although
proportions of the different photoproducts were similar in
vivo and in culture for both UVB and UVA, a major difference
was observed concerning the yields of formation in human skin.
Indeed, UVB induced 22-fold more bipyrimidine photoproducts in
keratinocyte cultures than in whole human skin, whereas UVA induced
1.5-fold lower CPDs in skin compared to cultured keratinocytes.
Thus, these authors demonstrated that UVA irradiation induced
larger amount of CPDs compared to oxidative DNA lesions, mainly at
TT sites, and that the multilayered structure of the skin afforded
a weak protection against UVA. The persistence of CPDs in
UVA-irradiated skin could reflect cell-cycle alteration or DNA
repair system degradation induced by UVA-oxidative stress.
CPDs, unlike oxidative DNA lesions such as 8-oxodGuo, are
probably major promutagenic DNA photoproducts for UVA radiation.
The authors suggest that CPD formation under UVA could be the
result of photosensitization rather than direct absorption of UVA
energy. Together, these data confirm the importance of UVA
radiation in skin photobiology and especially in skin
carcinogenesis. As UVA radiations constitute about 95% of the
natural sunlight exposure, it is of first importance to understand
the carcinogenic effects of UVA and to develop adequate high UVA
- Kappes UP, Luo D, Potter M, et al. Short- and
long-wave UV light (UVB and UVA) induce similar mutations in human
skin cells. J Invest
- Setlow RB, Grist E, Thompson K, et al. Wavelengths
effective in induction of malignant melanoma. Proc Natl Acad
Sci U S A 1993;90(14):6666-70.
- Stary A, Robert C, Sarasin A. Deleterious effects of
ultraviolet A radiation in human cells. Mutat
- de Laat A, van der Leun JC, de Gruijl FR. Carcinogenesis
induced by UVA (365 nm) radiation: the dose-time dependence of
tumor formation in hairless mice.
- Halliday GM. Inflammation, gene mutation and
photoimmunosuppression in response to UVR-induced oxidative damage
contributes to photocarcinogenesis. Mutat
- Agar NS, Halliday GM, Barnetson RS, et al. The basal
layer in human squamous tumours harbors more UVA than UVB
fingerprint mutations: a role for UVA in human skin carcinogenesis.
Proc Natl Acad Sci U S A 2004;101(14):4954-9.
- Mouret S, Baudouin C, Charveron M, et al. Cyclobutane
pyrimidine dimers are predominant DNA lesions in whole human skin
exposed to UVA radiation. Proc Natl Acad Sci U S