David Fisher及其同事报告,在一个小鼠模型中Mc1r的灭活在BRAFV600E存在时促进黑素瘤的形成,而与是否接受紫外线辐射无关。他们发现,正是“褐黑素”合成本身通过氧化性损伤的增加来促进黑素瘤形成的,因为使小鼠体内色素的生成完全停止便会消除这些效应。在实践上这说明,除避免阳光之外,进一步保护措施可能会对高危人士有好处。

-2012年11月15日《自然》

中文翻译


【题目】红色头发/白色皮肤背景下黑色素瘤致癌作用中的紫外线辐射非依赖途径

【译文】与所有其他色素沉着表型相比,具有白色皮肤、红色头发、雀斑以及无法晒成褐色,即红发/白肤表型的个体发展成黑色素瘤的风险最高。从遗传学上说,这种表型通常是黑色皮素1受体(MC1R)基因钝化多态性的产物。MC1R编码一种周期的AMP刺激G蛋白偶联受体,它可以控制色素的产生。例如在红发/白肤多态性中,最小限度受体活性就可以产生红/黄褐黑素,而增加MC1R活性会刺激黑/褐色真黑素。相对真黑素而言,褐黑素具有微弱遮蔽紫外辐射的能力,并有研究表明它能够提高紫外线A诱导的活性氧水平。然而,一些研究结果质疑了黑素瘤风险完全是由紫外线辐射引起的。例如,与非黑素瘤皮肤癌不同,黑素瘤不局限于阳光暴露的皮肤,而且紫外线辐射标志基因突变并不是常见的致癌驱动因素。尽管黑素瘤和紫外线辐射暴露之间的联系不容置疑,但紫外线辐射非依赖型事件好像也具有重要作用。本研究我们将最普遍黑素瘤癌蛋白BRAFV600E的条件性黑素细胞靶向的等位基因引入携带有失活突变Mc1r基因的小鼠中,这些小鼠具有类似于红发/白肤人类的表型。在没有提供附加基因畸变或紫外线照射暴露的前提下,我们观察到侵袭性黑素瘤在小鼠中具有高发病率。为了研究紫外线辐射非依赖性致癌作用的机制,我们引入一种白化等位基因,该基因可以消除在Mc1re/e背景下产生的色素。褐黑素合成的选择性缺失可以抵抗黑素瘤的发展。此外,我们发现与白化Mc1re/e小鼠皮肤相比,正常Mc1re/e小鼠皮肤具有明显更强的氧化性DNA和脂质损伤。这些数据表明褐黑素通路产生对黑素瘤的紫外线辐射非依赖型致癌作用,这是依赖一种氧化损伤的机制。 尽管防止紫外线辐射依旧非常重要,但额外的策略或许对于黑素瘤的预防也是必需的。

英文原稿


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

[Authors]:Devarati Mitra,1 Xi Luo,2 Ann Morgan,1 Jin Wang,3 Mai P. Hoang,4 Jennifer Lo,1 Candace R. Guerrero,3 Jochen K. Lennerz,5 Martin C. Mihm,4 Jennifer A. Wargo,6 Kathleen C. Robinson,1 Suprabha P. Devi,1 Jillian C. Vanover,7 John A. D’Orazio,7 Martin McMahon,8 Marcus W. Bosenberg,9 Kevin M. Haigis,2 Daniel A. Haber,2 Yinsheng Wang3 & David E. Fisher1

[Abstract]People with pale skin, red hair, freckles and an inability to tan—the ‘red hair/fair skin’ phenotype—are at highest risk of developing melanoma, compared to all other pigmentation types. 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. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. 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. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAFV600E, 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 Mc1re/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/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.

原文地址

http://www.nature.com/nature/journal/v491/n7424/full/nature11624.html

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