Molecular Pathogenic Mechanism of Rhabdomyosarcoma

PAX3-FKHR融合蛋白存在于大多数肺泡型横纹肌肉瘤中，与侵袭性增加和预后不良有关。为了更好地了解PAX3-FKHR的分子发病机制，我们首次在全基因组范围内无偏见地鉴定了肺泡型横纹肌肉瘤中PAX3-FKHR结合位点和相关靶基因。数据显示，PAX3-FKHR在MYF5和MYOD增强子上与PAX3结合在相同的位置。全基因组分析表明，PAX3-FKHR位点主要位于转录起始点的远端，(B)保守，(C)富含PAX3基序，(D)与PAX3-FKHR阳性横纹肌肉瘤细胞和肿瘤中过表达的基因密切相关。在我们的数据集中，几乎没有证据表明PAX3-FKHR与启动子序列结合。全基因组分析进一步表明，这些结合位点上的PAX3和E-box基序之间存在很强的关联，这表明许多靶基因存在共同的协同调节。我们还提供了第一个直接证据，证明FGFR4和IGF1R是PAX3-FKHR的靶标。PAX3-FKHR结合位点图为理解PAX3-FKHR的致病作用及其分子靶点提供了一个框架，从而可以系统地评估抗这种侵袭性横纹肌肉瘤的药物。我们的研究发表在《癌症研究》(曹等人，2010)上。它被NCI-Frederick Poster(2010年9月9日)引用为《白金出版物》的顶级论文，并被NCI的CCR(2011年1月1日)刊登在The Journal上。

The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHRpositive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. Our study was published in Cancer Research (Cao et al., 2010). It was cited at the Platinum Publications as a top paper by NCI-Frederick Poster (9/2010) and featured at In the Journal (1/2011) by CCR, NCI.