A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis
A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis
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DOI：
10.1158/0008-5472.can-06-3481
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Rodriguez-Peralto, Jose L.
中科院分区：
文献类型：
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作者：
Alonso, Soledad R.;Tracey, Lorraine;Rodriguez-Peralto, Jose L.
转移性疾病是皮肤恶性黑色素瘤（CMM）患者死亡的主要原因。为了了解CMM转移的机制并确定潜在的预测标志物，我们使用cDNA微阵列分析了34例垂直生长期黑色素瘤病例的基因表达谱。所有患者至少随访36个月。21例发生淋巴结转移，13例未发生。转移性和非转移性黑色素瘤病例的基因表达谱比较发现243个基因的差异表达比为b> 2倍，假发现率< 0.2（上调206个，下调37个）。这组基因包括参与细胞周期和凋亡调节、上皮-间质转化（EMT）、信号转导、核酸结合和转录、蛋白质合成和降解、代谢以及一组特定的黑色素瘤和神经相关蛋白的分子。在一系列独立的黑色素瘤中使用组织微阵列验证了这些表达数据，证实了EMT组中包含的一组蛋白质（n -钙粘蛋白、骨桥蛋白和SPARC/骨连接蛋白）的表达与转移的发展显著相关。我们的研究结果表明，emt相关基因通过支持特定的粘附性、侵袭性和迁移性，促进了原发性CMM的转移表型。这些数据使我们对这种侵袭性肿瘤的生物学有了更好的了解，除了潜在的治疗靶点外，还可能提供新的预后和患者分层标记。
Metastatic disease is the primary cause of death in cutaneous malignant melanoma (CMM) patients. To understand the mechanisms of CMM metastasis and identify potential predictive markers, we analyzed gene-expression profiles of 34 vertical growth phase melanoma cases using cDNA microarrays. All patients had a minimum follow-up of 36 months. Twenty-one cases developed nodal metastatic disease and 13 did not. Comparison of gene expression profiling of metastatic and nonmetastatic melanoma cases identified 243 genes with a > 2-fold differential expression ratio and a false discovery rate of < 0.2 (206 up-regulated and 37 down-regulated). This set of genes included molecules involved in cell cycle and apoptosis regulation, epithelial-mesenchymal transition (EMT), signal transduction, nucleic acid binding and transcription, protein synthesis and degradation, metabolism, and a specific group of melanoma- and neural-related proteins. Validation of these expression data in an independent series of melanomas using tissue microarrays confirmed that the expression of a set of proteins included in the EMT group (N-cadherin, osteopontin, and SPARC/osteonectin) were Significantly associated with metastasis development. Our results suggest that EMT-related genes contribute to the promotion of the metastatic phenotype in primary CMM by supporting specific adhesive, invasive, and migratory properties. These data give a better understanding of the biology of this aggressive tumor and may provide new prognostic and patient stratification markers in addition to potential therapeutic targets.