Loupe J M, Miller P J, Bonner B P, Maggi E C, Vijayaraghavan J, Crabtree J S, Taylor C M, Zabaleta J, Hollenbach A D
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Oncogenesis. 2016 Jul 25;5(7):e246. doi: 10.1038/oncsis.2016.53.
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.
横纹肌肉瘤是儿童期最常见的肉瘤之一，主要由两种亚型组成，即胚胎型和肺泡型（腺泡状横纹肌肉瘤，ARMS）。ARMS是侵袭性更强的亚型，其主要特征是发生t(2;13)(p35;p14)染色体易位，该易位使两个转录因子PAX3和FOXO1融合，产生致癌融合蛋白PAX3-FOXO1。PAX3-FOXO1阳性肿瘤患者预后较差，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能增加。尽管有这些认识，但对于致癌融合蛋白在这种增加的侵袭潜能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进行大规模比较转录组分析，以证明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。相比之下，PAX3的表达以预测抑制侵袭的方式改变60种mRNA和23种miRNA的表达。我们证明，mRNA和miRNA的这些改变转化为原代成肌细胞侵袭潜能的变化，PAX3-FOXO1使侵袭增加近2倍，而PAX3使侵袭减少近4倍。综上所述，这些结果使我们能够在前人报告的基础上，建立一个更广泛的分子模型，通过该模型PAX3-FOXO1的存在改变全局基因调控网络，以增强细胞的局部侵袭性。此外，我们观察到的变化的全局性突出了这样一个事实，即我们不应只关注单一基因靶点，而必须制定多方面的治疗方案，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。
