Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion.
Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion.
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DOI：
10.1038/oncsis.2016.53
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发表时间：
2016-07-25
期刊：
影响因子：
6.2
通讯作者：
Hollenbach AD
中科院分区：
文献类型：
--
作者：
Loupe JM;Miller PJ;Bonner BP;Maggi EC;Vijayaraghavan J;Crabtree JS;Taylor CM;Zabaleta J;Hollenbach AD
横纹肌肉瘤是最常见的儿童肉瘤之一，由两种主要亚型组成：胚胎型和肺泡型 (ARMS)。 ARMS 是更具攻击性的亚型，其主要特征是 t(2;13)(p35;p14) 染色体易位，它融合了两个转录因子 PAX3 和 FOXO1，生成致癌融合蛋白 PAX3-FOXO1。 PAX3-FOXO1阳性肿瘤患者的预后较差，部分原因是这些细胞的局部侵袭能力增强，导致该肿瘤的转移潜力增加。尽管有这些知识，但人们对致癌融合蛋白在这种增加的侵袭潜力中所起的作用知之甚少。在本报告中，我们在生理相关的原代成肌细胞中使用大规模比较转录组分析来证明 PAX3-FOXO1 的存在足以以预测促进细胞侵袭的方式改变 70 种 mRNA 和 27 种 miRNA 的表达。相反，PAX3 的表达以预测抑制入侵的方式改变 60 个 mRNA 和 23 个 miRNA。我们证明，mRNA 和 miRNA 的这些改变转化为原代成肌细胞侵袭潜力的变化，其中 PAX3-FOXO1 将侵袭增加近 2 倍，而 PAX3 将侵袭减少近 4 倍。总而言之，这些结果使我们能够在以前的报告的基础上开发出更广泛的分子模型，通过该模型，PAX3-FOXO1 的存在改变了全局基因调控网络，从而增强了细胞的局部侵袭性。此外，我们观察到的变化的全球性质凸显了这样一个事实：我们必须开发针对单一致癌表型的多个基因或针对肿瘤进展的不同致癌表型的多个基因的多方面治疗方案，而不是专注于单基因靶标。
Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.