Recio Juan A, Noonan Frances P, Takayama Hisashi, Anver Miriam R, Duray Paul, Rush Walter L, Lindner Gerd, De Fabo Edward C, DePinho Ronald A, Merlino Glenn
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892-4264, USA.
Cancer Res. 2002 Nov 15;62(22):6724-30.
Cutaneous malignant melanoma (CMM), already known for its highly aggressive behavior and resistance to conventional therapy, has evolved into a health crisis by virtue of a dramatic elevation in incidence. The underlying genetic basis for CMM, as well as the fundamental role for UV radiation in its etiology, is now widely accepted. However, the only bona fide genetic locus to emerge from extensive analysis of CMM suppressor candidates is INK4a/ARF at 9p21, which is lost frequently in familial and occasionally in somatic CMM. The functional relationship between INK4a/ARF and UV radiation in the pathogenesis of CMM is largely unknown. Recently, we reported that hepatocyte growth factor/scatter factor (HGF/SF)-transgenic mice develop melanomas after a single erythemal dose of neonatal UV radiation, supporting epidemiological data implicating childhood sunburn in CMM. Here we show that neonatal UV irradiation induces a full spectrum of melanocyte pathology from early premalignant lesions through distant metastases. Cutaneous melanomas arise with histopathological and molecular pathogenetic features remarkably similar to CMM, including loss of ink4a/arf. A role for ink4a/arf in UV-induced melanomagenesis was directly assessed by placing the HGF/SF transgene on a genetic background devoid of ink4a/arf. Median time to melanoma development induced by UV radiation was only 50 days in HGF/SF ink4a/arf(-/-) mice, compared with 152 and 238 days in HGF/SF ink4a/arf(+/-) and HGF/SF ink4a/arf(+/+) mice, respectively. These studies provide experimental evidence that ink4a/arf plays a critical role in UV-induced melanomagenesis and strongly suggest that sunburn is a highly significant risk factor, particularly in families harboring germ-line mutations in INK4a/ARF.
皮肤恶性黑色素瘤（CMM）因其高度侵袭性的行为和对传统治疗的抗性而闻名，如今发病率急剧上升，已演变成一场健康危机。CMM的潜在遗传基础以及紫外线辐射在其病因学中的基本作用，现已被广泛接受。然而，在对CMM抑制候选基因进行广泛分析后，唯一真正出现的遗传位点是位于9p21的INK4a/ARF，它在家族性CMM中经常缺失，在散发性CMM中偶尔缺失。INK4a/ARF与紫外线辐射在CMM发病机制中的功能关系在很大程度上尚不清楚。最近，我们报道肝细胞生长因子/分散因子（HGF/SF）转基因小鼠在单次红斑剂量的新生儿紫外线辐射后会发生黑色素瘤，这支持了将儿童晒伤与CMM联系起来的流行病学数据。在此我们表明，新生儿紫外线照射会引发从早期癌前病变到远处转移的全谱黑素细胞病理变化。皮肤黑色素瘤出现时具有与CMM显著相似的组织病理学和分子致病特征，包括ink4a/arf缺失。通过将HGF/SF转基因置于缺乏ink4a/arf的遗传背景上，直接评估了ink4a/arf在紫外线诱导的黑色素瘤发生中的作用。在HGF/SF ink4a/arf（-/-）小鼠中，紫外线辐射诱导黑色素瘤发生的中位时间仅为50天，而在HGF/SF ink4a/arf（+/-）和HGF/SF ink4a/arf（+/+）小鼠中分别为152天和238天。这些研究提供了实验证据，表明ink4a/arf在紫外线诱导的黑色素瘤发生中起关键作用，并强烈表明晒伤是一个高度重要的风险因素，特别是在携带INK4a/ARF种系突变的家族中。
