The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486
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Nature Publishing Group
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The alveolar subtype (ARMS) is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 that drives oncogenic cellular properties. Exosomes are small, secreted vesicles that affect paracrine signaling. We show that PAX3-FOXO1 transcript alters exosome content of C2C12 myoblasts, leading to pro-tumorigenic paracrine effects in recipient cells. Microarray analysis revealed alteration in miRNA content of exosomes, affecting cellular networks involved in cell metabolism, growth signaling, and cellular invasion. Overexpression and knockdown studies showed that miR-486-5p is an effector of PAX3-FOXO1, and mediates its paracrine effects in exosomes, including promoting recipient cell migration, invasion, and colony formation. Analysis of human RMS cells showed miR-486-5p is enriched in both cells and exosomes, and to a higher extent in ARMS subtypes. Analysis of human serum samples showed that miR-486-5p is enriched in exosomes of patients with RMS, and follow-up after chemotherapy showed decrease to control values. Our findings identify a novel role of both PAX3-FOXO1 and its downstream effector miR-486-5p in exosome-mediated oncogenic paracrine effects of RMS, and suggest its possible use as a biomarker. © 2019, The Author(s).
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Animals, Antineoplastic combined chemotherapy protocols, Biomarkers, tumor, Cell adhesion, Cell division, Cell line, Exosomes, Gene expression regulation, neoplastic, Gene knockdown techniques, Humans, Mice, Mice, inbred c57bl, Microarray analysis, Micrornas, Myoblasts, Neoplasm invasiveness, Oncogene proteins, fusion, Paired box transcription factors, Paracrine communication, Recombinant proteins, Rhabdomyosarcoma, alveolar, Rna, neoplasm, Soft tissue neoplasms, Transduction, genetic, Antineoplastic agent, Microrna, Mirn486 microrna, human, Oncoprotein, Paired box transcription factor, Pax3-foxo1a fusion protein, human, Recombinant protein, Rna, Tumor marker, Animal, Blood, C57bl mouse, Exosome, Gene expression regulation, Gene knockdown, Genetic transduction, Genetics, Human, Metabolism, Mouse, Myoblast, Paracrine signaling, Physiology, Rhabdomyosarcoma, Soft tissue tumor, Tumor invasion, Ultrastructure