An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background

作者：Mitra Devarati; Luo Xi; Morgan Ann; Wang Jin; Hoang Mai P; Lo Jennifer; Guerrero Candace R; Lennerz Jochen K; Mihm Martin C; Wargo Jennifer A; Robinson Kathleen C; Devi Suprabha P; Vanover Jillian C; D' Orazio John A; McMahon Martin; Bosenberg Marcus W; Haigis Kevin M; Haber Daniel A; Wang Yinsheng; Fisher David E^*

来源：Nature, 2012, 491(7424): 449-+.

DOI：10.1038/nature11624

People with pale skin, red hair, freckles and an inability to tan-the %26apos;red hair/fair skin%26apos; phenotype-are at highest risk of developing melanoma, compared to all other pigmentation types(1). Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin(2). Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species(3-5). Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers(6). Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role(1,7). Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.

• 出版日期2012-11-15