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Cellular and Molecular
Changes during Photocarcinogenesis.
Ananthaswamy, Honnavara1,
Pacifico, Alessia1,3, Ouhtit, Allal1,
Bolshakov, Svetlana1, Chimenti, Sergio2
and Peris, Ketty3
M.D. Anderson Cancer Center, Houston, Texas, USA1
University of Tor Vergata, Rome, Italy2
University of l'Aquila, l'Aquila, Italy3
Abstract-
Exposure of the skin to ultraviolet (UV) radiation causes overexpression
of p53, which in turn upregulates genes that cause growth arrest. The
p53 protein is also involved in programmed cell death (apoptosis) aimed
at eliminating cells with excessive DNA damage. Following repeated exposures
to UV, keratinocytes carrying p53 mutations acquire a growth
advantage by virtue of their increased resistance to apoptosis. Additional
exposure to UV can cause mutations in the other p53 allele and/or
other gene(s), thus leading to the initiation and progression of skin
cancer. Our previous studies showed that p53 mutations in UV-irradiated
mouse skin arise very early and well before tumor development. In this
study, we investigated the rate of UV-induced p53 mutation after discontinuation
of chronic UV irradiation. Hairless SKH-hr1 mice were exposed to chronic
UV (2.5 kJ/m2, 3X/wk) for 8 wk from Kodacel-filtered FS40 sunlamps and
analyzed for p53 mutations at various times after discontinuation
of UV treatment. The results indicated that 100% of mice irradiated
with UV for 8 wk had p53 mutations at one or more hotspot codons.
However, discontinuation of irradiation after 8 wk of chronic UV resulted
in a gradual disappearance of p53 mutations in a time dependent
manner. At 10 wk after cessation of UV treatment, none of the mice had
p53 mutations in their epidermis. The kinetics of disappearance
of p53 mutations paralled disappearance of epidermal hyperplasia
caused by chronic UV irradiation. These results suggest that keratinocytes
containing UV-induced p53 mutations have a limited life span
and they disappear from the skin if they are not subjected to further
UV irradiation. However, mutations in p53 or other genes may
still be present in a few UV damaged keratinocytes and those cells may
be predisposed to skin cancer development. This hypothesis is supported
by the finding that about 5% of the mice developed skin tumors in the
head and neck region even after discontinuation of UV, and those tumors
had UV signature p53 mutations. This implies that the risk of
skin cancer can be reduced but not completely abolished upon further
avoidance to UV exposure.
Keywords: apoptosis,
chronic UV exposure, photocarcinogenesis, skin cancer
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