Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis
Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis
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DOI：
10.1073/pnas.1004602107
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发表时间：
2010-05-25
影响因子：
11.1
通讯作者：
Scott, Matthew P.
中科院分区：
文献类型：
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作者：
Lee, Eunice Y.;Ji, Hongkai;Scott, Matthew P.
许多基因最初被鉴定为在发育过程中的细胞命运决定或信号传导中的作用，可对肿瘤发生产生重大影响。在发育中的小脑中，Sonic hedgehog（Shh）通过激活Gli转录因子刺激颗粒神经元前体细胞（GNP）的增殖。Shh靶基因的不适当激活会导致细胞分裂不受限制，最终导致髓母细胞瘤，这是最常见的小儿脑恶性肿瘤。我们发现GNP和髓母细胞瘤中Gli1转录因子直接驱动的基因网络存在显著差异。Gli1结合位点分析显示，Gli1在正常和癌细胞中结合了数百个基因组位点。GNP中Gli1结合的基因中只有三分之一也结合在肿瘤细胞中。与基因表达水平的相关性表明，116个基因在肿瘤中优先转录，而132个基因是GNP和髓母细胞瘤的靶基因。定量PCR和原位杂交的一些推定的靶基因支持Gli的直接调控。结果表明，正常GNP转化为致命的肿瘤细胞伴随着一组独特的GLI调节基因，并可能为靶向治疗提供候选人。
Many genes initially identified for their roles in cell fate determination or signaling during development can have a significant impact on tumorigenesis. In the developing cerebellum, Sonic hedgehog (Shh) stimulates the proliferation of granule neuron precursor cells (GNPs) by activating the Gli transcription factors. Inappropriate activation of Shh target genes results in unrestrained cell division and eventually medulloblastoma, the most common pediatric brain malignancy. We find dramatic differences in the gene networks that are directly driven by the Gli1 transcription factor in GNPs and medulloblastoma. Gli1 binding location analysis revealed hundreds of genomic loci bound by Gli1 in normal and cancer cells. Only one third of the genes bound by Gli1 in GNPs were also bound in tumor cells. Correlation with gene expression levels indicated that 116 genes were preferentially transcribed in tumors, whereas 132 genes were target genes in both GNPs and medulloblastoma. Quantitative PCR and in situ hybridization for some putative target genes support their direct regulation by Gli. The results indicate that transformation of normal GNPs into deadly tumor cells is accompanied by a distinct set of Gli-regulated genes and may provide candidates for targeted therapies.