DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma
DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma
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DOI：
10.1158/1078-0432.ccr-04-1941
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发表时间：
2005-05-15
影响因子：
11.5
通讯作者：
Harbour, JW
中科院分区：
文献类型：
--
作者：
Ehlers, JP;Worley, L;Harbour, JW
目的：葡萄膜黑色素瘤的分子发病机制知之甚少，但通常伴有染色体8q的扩增，提示一个或多个癌基因的激活。我们最近确定了一个基因表达谱，区分从高级别低级别黑色素瘤。在这个配置文件中，在染色体8q的基因簇在高级别的肿瘤过表达，提供了一个机会，以寻找潜在的癌基因在这个region.Experimental设计：基因表达微阵列分析25原发性葡萄膜黑色素瘤。微阵列比较基因组杂交（CGH），定量PCR和免疫组化进行了这些肿瘤的一个子集。使用伤口愈合assay.Results：在黑色素瘤微阵列基因表达和CGH分析，染色体8q的增益与DDEF 1，位于8q24的基因的表达相关性最强。相比之下，附近的MYC癌基因的表达没有显着变化。与微阵列结果一致，DDEF 1 mRNA水平和蛋白表达在高级别黑色素瘤中显著较高。此外，异位表达的DDEF 1在低级别的黑色素瘤细胞中导致细胞运动，高级别的metastasizing cells.Conclusions的一个功能显着增加：这些研究结果表明，DDEF 1过表达可能是一个病理相关的后果染色体8q扩增，这通常发生在高级别葡萄膜黑色素瘤。结论DDEF 1可能作为癌基因在乳腺癌中发挥作用，它可能是一个有用的诊断标志物和治疗靶点。
Purpose: The molecular pathogenesis of uveal melanoma is poorly understood but is usually accompanied by amplification of chromosome 8q, suggesting the activation of one or more oncogenes. We recently identified a gene expression profile that distinguishes low-grade from high-grade melanomas. In this profile, a cluster of genes at chromosome 8q was overexpressed in high-grade tumors, providing an opportunity to search for potential oncogenes in this region.Experimental Design: Gene expression microarray analysis was done on 25 primary uveal melanomas. Microarray comparative genomic hybridization (CGH), quantitative PCR, and immunohistochemistry were done on a subset of these tumors. Cell motility was measured using a wound-healing assay.Results: In melanomas analyzed for microarray gene expression and CGH, gain of chromosome 8q correlated most strongly with expression of DDEF1, a gene located at 8q24. In contrast, the nearby MYC oncogene exhibited no significant change in expression. Confirming the microarray findings, DDEF1 mRNA levels and protein expression were significantly higher in high-grade melanomas. Furthermore, ectopic expression of DDEF1 in low-grade melanoma cells resulted in a significant increase in cell motility, a feature of high-grade metastasizing cells.Conclusions: These findings suggest that DDEF1 overexpression may be a pathogenetically relevant consequence of chromosome 8q amplification, which commonly occurs in high-grade uveal melanomas. We conclude that DDEF1 may act as an oncogene in this cancer, and it may be a useful diagnostic marker and therapeutic target.