Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature
Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature
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DOI：
10.1111/j.1600-0749.2006.00322.x
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发表时间：
2006-08-01
期刊：
影响因子：
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通讯作者：
Dummer, Reinhard
中科院分区：
文献类型：
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作者：
Hoek, Keith S.;Schlegel, Natalie C.;Dummer, Reinhard
黑色素瘤转移潜能的分子生物学已经被研究了很多次，许多基因表达的变化与转移行为有关。缺乏对基因之间调控关系的系统描述，这些基因的表达与转移潜能有关。这样的特征将产生黑色素瘤的分子分类，可以可行地用于识别转移行为变化背后的表观遗传机制。为了实现这一点，我们对总共86种黑色素瘤培养物进行了三种不同的DNA微阵列分析。值得注意的是，多重检验修正表明，以前描述基因表达与BRAF或NRAS激活突变的相关性的报道是不正确的，没有基因表达模式与这些MAPK途径组件的突变状态相关。相反，我们确定了三个不同的样本队列(A、B和C)，并发现这些队列代表了不同转移潜力的黑色素瘤组。A组和B组对转化生长因子-β(TGF-β)介导的增殖抑制敏感，且运动能力低。队列C对转化生长因子β具有抵抗力，表现出较高的运动能力。将这些数据与先前将基因表达和表型联系起来的研究进行荟萃分析，证实了队列A和C分别代表弱转移性和强转移性黑色素瘤的转录特征。基因表达的共同调节表明，通过转化生长因子β-型和Wnt/β-连环蛋白通路的信号在队列之间经历了相当大的变化。这些结果提示了一种从弱转移性黑色素瘤到强转移性黑色素瘤的模型，在该模型中，转化生长因子β信号上调了表达血管生成/细胞外基质重塑因子和Wnt信号抑制因子的基因，同时下调了Wnt信号下游的基因。
The molecular biology of metastatic potential in melanoma has been studied many times previously and changes in the expression of many genes have been linked to metastatic behaviour. What is lacking is a systematic characterization of the regulatory relationships between genes whose expression is related to metastatic potential. Such a characterization would produce a molecular taxonomy for melanoma which could feasibly be used to identify epigenetic mechanisms behind changes in metastatic behaviour. To achieve this we carried out three separate DNA microarray analyses on a total of 86 cultures of melanoma. Significantly, multiple testing correction revealed that previous reports describing correlations of gene expression with activating mutations in BRAF or NRAS were incorrect and that no gene expression patterns correlate with the mutation status of these MAPK pathway components. Instead, we identified three different sample cohorts (A, B and C) and found that these cohorts represent melanoma groups of differing metastatic potential. Cohorts A and B were susceptible to transforming growth factor-beta (TGF beta)-mediated inhibition of proliferation and had low motility. Cohort C was resistant to TGF beta and demonstrated high motility. Meta-analysis of the data against previous studies linking gene expression and phenotype confirmed that cohorts A and C represent transcription signatures of weakly and strongly metastatic melanomas, respectively. Gene expression co-regulation suggested that signalling via TGF beta-type and Wnt/beta-catenin pathways underwent considerable change between cohorts. These results suggest a model for the transition from weakly to strongly metastatic melanomas in which TGF beta-type signalling upregulates genes expressing vasculogenic/extracellular matrix remodelling factors and Wnt signal inhibitors, coinciding with a downregulation of genes downstream of Wnt signalling.