Molecular Pathogenic Mechanism of Rhabdomyosarcoma

横纹肌肉瘤的分子发病机制

• 批准号: 9153812
• 负责人: Liang Cao
• 金额: $ 1.61万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153812
• 关键词: Alveolar Rhabdomyosarcoma; Binding; Binding Sites; Biological Markers; Biological Models; Boxing; Cell model; Cells; Chimeric Proteins; Data; Data Set; Development; Distal; Drug Targeting; E-Box Elements; Embryonic Development; Enhancers; Evaluation; FGFR4 gene; FOXO1A gene; Family; Gene Rearrangement; Gene Targeting; Genes; Goals; HDAC5 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; IGF1R gene; Immune system; Kidney; Maintenance; Malignant Neoplasms; Manuscripts; Maps; Modification; Molecular; Molecular Target; Muscle; Mutation; Neural Crest; Neuraxis; Organogenesis; PAX3 gene; PAX7 gene; Pancreas; Pathogenesis; Process; Rhabdomyosarcoma; Role; Site; Skeletal Muscle; Stem cells; Stream; Therapeutic Intervention; Tissues; Transcription Initiation Site; Transcriptional Regulation; Translating; cell motility; epigenomics; genome-wide analysis; human disease; member; neoplastic cell; new therapeutic target; outcome forecast; overexpression; preclinical evaluation; programs; promoter; response; transcription factor; tumor

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 (Cao et al., 2010). Some of our current studies are aim to understand the transcription regulation of PAX3 and PAX3-FKHR expression via the analysis of their epigenomic modification. Also, PAX3-FKHR up-regulates a HDAC gene which we have showed to be essential for the survival of rhabdomyosarcoma cells. We are exploring the possibility of using this information for the preclinical evaluation of HDAC inhibitors against the tumor and the identification of biomarkers predictive of response to this class of agents. We have established that HDAC5 is a down-stream target and a potential drug target. We are the process of preparing a manuscript.

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，从而能够系统地评估抗这种侵袭性横纹肌肉瘤的药物(曹等人，2010年)。我们目前的一些研究旨在通过分析PAX3和PAX3-FKHR的表观基因组修饰来了解它们的转录调控。此外，PAX3-FKHR上调HDAC基因，我们已经证明该基因对横纹肌肉瘤细胞的生存是必不可少的。我们正在探索将这些信息用于HDAC抑制剂抗肿瘤的临床前评估的可能性，并识别预测对这类药物的反应的生物标志物。我们已经确定HDAC5是一个下游靶点和潜在的药物靶点。我们正在准备一份手稿。