Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures.
Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16(Ink4a) expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf-, Xpa- knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1 x /2 weeks > 4 MED 1 x /wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice. Ink4a/Arf(-/-) mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf(-/-) mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf(-/-) genotype may actually impair nevus development.
van Schanke
Arne
A
Dermatology Department, University Medical Centre Utrecht, Utrecht, the Netherlands.
van Venrooij
Gemma M C A L
GM
Jongsma
Marjan J
MJ
Banus
H Alexander
HA
Mullenders
Leon H F
LH
van Kranen
Henk J
HJ
de Gruijl
Frank R
FR
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics; D003043:Cocarcinogenesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D008546:Melanoma, Experimental / Q000209:etiology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D009506:Nevus / Q000209:etiology* / Q000235:genetics; D012509:Sarcoma / Q000209:etiology / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics*; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene