Rhabdomyosarcoma is a pediatric cancer associated with aggressiveness and a tendency to develop metastases. Fusion-negative rhabdomyosarcoma (FN-RMS) is the most commonly occurring subtype of RMS, where metastatic disease can hinder treatment success and decrease survival rates. RMS-derived exosomes were previously demonstrated to be enriched with miRNAs, including miR-1246, possibly contributing to disease aggressiveness. We aimed to decipher the functional impact of exosomal miR-1246 on recipient cells and its role in promoting aggressiveness. Treatment of normal fibroblasts with FN-RMS-derived exosomes resulted in a significant uptake of miR-1246 paired with an increase in cell proliferation, migration, and invasion. In turn, delivery of miR-1246-mimic lipoplexes promoted fibroblast proliferation, migration, and invasion in a similar manner. Conversely, when silencing miR-1246 in FN-RMS cells, the resulting derived exosomes demonstrated reversed effects on recipient cells’ phenotype. Delivery of exosomal miR-1246 targetsGSK3βand promotes β-catenin nuclear accumulation, suggesting a deregulation of the Wnt pathway, known to be important in tumor progression. Finally, a pilot clinical study highlighted, for the first time, the presence of high exosomal miR-1246 levels in RMS patients’ sera. Altogether, our results demonstrate that exosomal miR-1246 has the potential to alter the tumor microenvironment of FN-RMS cells, suggesting its potential role in promoting oncogenesis.
横纹肌肉瘤是一种与侵袭性和转移倾向相关的儿童恶性肿瘤。融合阴性横纹肌肉瘤是该疾病最常见的亚型，其转移性病变可能阻碍治疗成功并降低生存率。先前研究表明，横纹肌肉瘤来源的外泌体富含包括miR-1246在内的多种miRNA，这可能与疾病侵袭性相关。本研究旨在解析外泌体miR-1246对受体细胞的功能影响及其在促进侵袭性中的作用机制。使用融合阴性横纹肌肉瘤来源的外泌体处理正常成纤维细胞后，可观察到miR-1246的显著摄取，并伴随细胞增殖、迁移和侵袭能力的增强。相应地，通过脂质复合体递送miR-1246模拟物也能以类似方式促进成纤维细胞的增殖、迁移和侵袭。反之，当沉默融合阴性横纹肌肉瘤细胞中的miR-1246时，其产生的外泌体对受体细胞表型的影响发生逆转。外泌体miR-1246通过靶向GSK3β并促进β-catenin核积累发挥作用，表明其对已知在肿瘤进展中至关重要的Wnt通路具有调控作用。最后，一项初步临床研究首次揭示横纹肌肉瘤患者血清中存在高水平的外泌体miR-1246。综上所述，我们的研究结果表明外泌体miR-1246具有改变融合阴性横纹肌肉瘤细胞肿瘤微环境的潜力，提示其在促进肿瘤发生中可能发挥重要作用。
肿瘤(癌症)患者之家