Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors.
Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors.
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WT1 突变肿瘤中 c-MYC 的上调：使用基因定义的肾母细胞瘤的 cDNA 微阵列表达谱评估 WT1 假定的转录靶标。
DOI：
10.1038/sj.onc.1206597
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Huff,Vicki
中科院分区：
文献类型：
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作者：
Udtha,Malini;Lee,Sang-Joon;Alam,Rita;Coombes,Kevin;Huff,Vicki
Wilms肿瘤抑制基因WT1是一种转录调节因子，可抑制或激活多种预期靶基因的表达。然而，目前尚不清楚哪些基因是WT1的生物学靶点，也不清楚肿瘤中哪些细胞通路因WT1突变而发生严重改变。为了在体内研究WT1作为转录因子在Wilms肿瘤中的作用，我们使用cDNA微阵列比较了15例携带WT1失活突变的原发Wilms肿瘤和16例未携带WT1突变的原发Wilms肿瘤中假定的WT1靶基因的表达。我们假设与肿瘤发展相关的WT1的直接下游靶点的表达在这两组遗传上不同的肿瘤中是不同的。利用Atlas Human Cancer 1.2 cDNA阵列对31例肿瘤中的基因表达进行定量分析，我们发现两组肿瘤中WT1推定靶基因c-MYC的表达差异有统计学意义，并且在WT1突变肿瘤中表达上调。实时逆转录-聚合酶链反应证实了c-MYC基因相对表达量的增加。另一个假定的靶基因EGR1的差异表达在wt1突变的肿瘤中接近显著，并且也上调。这些数据，加上胚胎肾间质中c-MYC和WT1的共表达，强烈提示c-MYC是wilmstoms中WT1的生物学相关靶点。
The Wilms' tumor suppressor gene, WT1, functions as a transcriptional regulator that represses or activates the expression of a variety of putative target genes. However, it is not clear which genes are the biological targets of WT1, nor which cellular pathway (s) is critically altered in tumors as a result of WT1 mutation. To investigate in vivo the role of WT1 as a transcription factor in Wilms' tumors, we used cDNA microarrays to compare the expression of putative WT1 target genes in a set of 15 primary Wilmstumors carrying WT1-inactivating mutations versus a set of 16 tumors with no WT1 mutations. We hypothesized that the expression of direct downstream targets of WT1 that are relevant to tumor development would differ between these two genetically distinct sets of tumors. Using the Atlas Human Cancer 1.2 cDNA arrays to quantitate gene expression in the 31 tumors, we found that the expression of one WT1 putative target gene, c-MYC, statistically significantly differed between the two sets of tumors and was upregulated in WT1-mutant tumors. This increase of relative gene expression for c-MYC was confirmed using real-time reverse transcription–polymerase chain reaction. The differential expression of another putative target gene, EGR1, approached significance and was also upregulated in WT1-mutant tumors. These data, in addition to the coexpression of c-MYC and WT1 in embryonic renal mesenchyme, strongly suggest that c-MYC is a biologically relevant target of WT1 in Wilmstumors.