Reduced expression of IL-18 is a marker of ultraviolet radiation-induced melanomas.
We previously showed that mice carrying an activated Cdk4 mutation together with melanocyte-specific mutant Hras (Cdk4(R24C/R24C)/TPras) develop melanoma spontaneously, but penetrance is increased and age of onset reduced after neonatal ultraviolet radiation (UVR) exposure. UVR-treated mice were more likely to develop multiple primary lesions, and these melanomas more often expressed Trp53, and less often expressed c-Myc, than melanomas from nonirradiated mice (Hacker et al., Cancer Res 2006;66:2946-52). These data suggest differences in mechanisms of tumorigenesis between melanomas developing spontaneously, or as a result of UVR exposure. To further delineate these differences, we compared global gene expression between spontaneous and UVR-induced melanomas from these mice using microarrays. We found 264 genes differentially expressed between these groups (ANOVA, p < 0.05). Selected candidate genes were validated using qRT-PCR, which confirmed upregulation of Gpr155 and Bmp7, and downregulation of Plagl1, Akap12 and Il18 in UVR-induced mouse melanomas. In humans, epidemiological studies suggest that there may be 2 predominant pathways to melanoma development. One characterized by chronic UVR exposure and which leads mainly to melanomas on sun-exposed sites; the other associated with low UVR exposure and leading predominantly to melanomas on less-exposed body sites. We found by immunohistochemical analysis that, comparing a series of human melanomas from the head (a chronically sun-exposed site; N = 82) with a set from the trunk (an intermittently exposed site; N = 65), the prevalence of IL-18 expression was significantly lower in melanomas on the head (16%) than on truncal melanomas (34%, p = 0.011). We conclude that loss of IL-18 is a marker of UVR-induced melanoma, both in animal models and humans.
Hacker
Elke
E
Oncogenomics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Muller
Konrad
K
Whiteman
David C
DC
Pavey
Sandra
S
Hayward
Nicholas
N
Walker
Graeme
G
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020382:Interleukin-18 / Q000378:metabolism*; D008545:Melanoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays / Q000009:adverse effects*
D014408:Biomarkers, Tumor; D020382:Interleukin-18; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf