PAX3-FOXO1致癌基因改变外泌体miRNA含量，并导致由外泌体miR-486介导的旁分泌作用。,Scientific Reports

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PAX3-FOXO1致癌基因改变外泌体miRNA含量，并导致由外泌体miR-486介导的旁分泌作用。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-10-02 , DOI: 10.1038/s41598-019-50592-4
Farah Ghamloush ₁ , Sandra E Ghayad ₂ , Ghina Rammal _{2,

3} , Assil Fahs _{2,

3} , Abeer J Ayoub _{2,

3} , Zeina Merabi ₁ , Mohamad Harajly ₁ , Hassan Zalzali ₁ , Raya Saab _{1,

3}

Affiliation

横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤。肺泡亚型（ARMS）在临床上更具侵略性，其特征是驱动致癌细胞特性的致癌融合蛋白PAX3-FOXO1。外泌体是小的分泌性囊泡，会影响旁分泌信号传导。我们显示，PAX3-FOXO1成绩单改变C2C12成肌细胞的外泌体含量，导致受体细胞中促肿瘤的旁分泌作用。微阵列分析揭示了外泌体中miRNA含量的变化，影响了参与细胞代谢，生长信号传导和细胞侵袭的细胞网络。过度表达和基因敲除研究表明miR-486-5p是PAX3-FOXO1的效应子，并在外泌体中介导其旁分泌作用，包括促进受体细胞迁移，侵袭和集落形成。对人RMS细胞的分析表明，miR-486-5p在细胞和外泌体中都富集，并且在ARMS亚型中含量更高。对人体血清样品的分析表明，miR-486-5p在RMS患者的外泌体中富集，化学疗法后的随访结果显示降至对照值。我们的发现确定了PAX3-FOXO1及其下游效应物miR-486-5p在外来体介导的RMS致癌旁分泌作用中的新型作用，并暗示了其可能用作生物标记物。

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The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486.

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.

更新日期：2019-10-02

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