Induction of Nevi and Skin Tumors in Ink4a/Arf Xpa Knockout Mice by Neonatal, Intermittent, or Chronic UVB Exposures

Abstract

Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16Ink4a expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/ArfÀ, XpaÀ knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)

Loss of Xeroderma Pigmentosum C (Xpc) Enhances Melanoma Photocarcinogenesis in Ink4a-Arf–Deficient Mice

“…After a single high-dose UVB irradiation, two phenotypes were observed. Benign, proliferative cysts, which has been previously described (15), occurred with high penetrance when either Xpc or Ink4a-Arf were genetically ablated; concurrent deletion of both loci did not seem to enhance cyst formation. A second stochastically independent phenotype is that of cancer formation.…”

“…It is also instructive to compare and contrast our results with those published by van Schanke et al (15). The Xpa À/À /Ink4a-Arf À/À mice that were used in that study were generated on a Hairless (Hr) background.…”

“…A recent report described a low rate of melanoma tumor formation in Xpa À/À Ink4a-Arf À/À -deficient pigmented hairless mice treated with various combinations of topical DMBA, neonatal UV irradiation, and adult UV irradiation (15). Multiple melanocytic nevi, which have been described in chemical and UV-treated hairless mice, and six spindle-cell melanomas developed in 316 mice, although the melanomas were not associated with any specific treatment or genotype.…”

Ultraviolet Light as a Modulator of Melanoma Development

“…Naevus development was dramatically increased by Xpa deletion, implicating UVB-induced pyrimidine dimer-type mutations in the pathogenesis of the lesions. Consistent with human melanoma, where intermittent exposures are most important, a single high dose erythemal exposure was much more effective at inducing naevi than the same dose delivered daily in a fractionated regimen (van Schanke et al, 2006). In terms of using adult mice for UVR studies, a major problem is that they do not have epidermal melanocytes (and murine melanomas that develop are mostly dermal).…”

A Case of Huge Intradermal Melanocytic Nevus of the External Auditory Canal Orifice

“…4 Some authors asserts that overexposure to ultraviolet light from the sun may play a role in the skin damage that can lead to melanoma and the formation of acquired MN. 6 And the number of moles a person has was found to have a correlation with telomere length which may be of significance in the ageing process.…”