An oncogenic role for ETV1 in melanoma.
An oncogenic role for ETV1 in melanoma.
复制标题
DOI：
10.1158/0008-5472.can-09-3092
复制
发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Jané-Valbuena J;Widlund HR;Perner S;Johnson LA;Dibner AC;Lin WM;Baker AC;Nazarian RM;Vijayendran KG;Sellers WR;Hahn WC;Duncan LM;Rubin MA;Fisher DE;Garraway LA
在黑色素瘤中发现的最常见的基因组改变之一是涉及7p染色体的复制增加，这表明存在“驱动”癌症基因。我们鉴定了几个肿瘤样本，它们的焦点扩增位于共同染色体7p增益的峰值，其中最小的共同重叠区域跨越了ETV1癌基因。荧光原位杂交(FISH)分析显示，40%的病例出现ETV1基因的拷贝扩增，其中13%的原发黑色素瘤和18%的转移性黑色素瘤存在ETV1扩增。黑色素瘤细胞系，包括那些ETV1扩增的黑色素瘤细胞系，表现出对ETV1表达的增殖和锚定非依赖性生长的依赖性。此外，ETV1的过度表达与致癌基因NRASG12D一起转化了原代黑素细胞，并促进了小鼠肿瘤的形成。ETV1的过表达增加了永生化黑素细胞中MITF的表达，这是ETV1依赖的致癌所必需的。这些观察结果表明，ETV1在黑色素瘤的发生中被解除调控，并暗示在这种恶性疾病中，由致癌ETS转录因子介导的关键家族依赖性。
Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of “driver” cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization (FISH) analysis revealed copy gains spanning the ETV1 locus in >40% of cases, with ETV1 amplification present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage-independent growth. Moreover, over-expression of ETV1 in combination with oncogenic NRASG12D transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated MITF expression in immortalized melanocytes, which was necessary for ETV1-dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy.