Molecular Pathogenic Mechanism of Rhabdomyosarcoma

PAX3-FKHR融合蛋白存在于大多数与侵袭性增加和预后不良相关的肺泡横纹肌肉瘤中。为了更好地了解PAX3-FKHR的分子发病机制，我们首次在肺泡横纹肌肉瘤中进行了PAX3-FKHR结合位点和相关靶基因的全基因组鉴定。数据显示，PAX3- fkhr在MYF5和MYOD增强子上与PAX3结合在相同的位点上。全基因组分析显示，PAX3- fkhr位点(a)大多位于转录起始位点远端，(b)保守，(c) PAX3基元富集，(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，很少有证据表明PAX3-FKHR在启动子序列上结合。全基因组分析进一步说明了PAX3和这些结合位点上的E-box基序之间的强关联，提示了许多靶基因的共同协同调节。我们还提供了第一个直接证据，证明FGFR4和IGF1R是PAX3-FKHR的靶点。PAX3-FKHR结合位点图谱为了解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针对这种侵袭性横纹肌肉瘤的药物。我们的研究发表在Cancer Research （Cao et al., 2010）。该论文被NCI- frederick Poster（2010年9月）引用为白金出版物的顶级论文，并被NCI CCR（2011年1月）刊登在In 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.