Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR‐143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR‐145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR‐143/145, and its depletion phenotypically resembled miR‐143/145 upregulation in vitro. Last, FSCN1 is a malignancy‐promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR‐143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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miR-143/145 簇是一种新型软骨肉瘤诊断生物标志物，可作为肿瘤抑制剂并直接抑制 Fascin-1。

软骨肉瘤是第二常见的骨肉瘤。由于固有的化学疗法和放射疗法抗性以及缺乏已知的治疗靶点，临床管理仅限于手术切除。因此，晚期疾病患者的预后较差。因此，阐明控制软骨肉瘤发病机制的调控网络对于制定有效的治疗策略至关重要。在这里，结合计算机生物信息学工具对不同亚型人类软骨形成肿瘤的 miRNA 和 mRNA 进行下一代测序，旨在确定关键分子因素。我们确定了与肿瘤分级呈负相关的 miR-143/145 簇水平。这种失调在患者的 miRNA 血浆水平中得到了回应，我们提供了第一个证据，证明循环 miR-145 是一种潜在的非侵入性诊断生物标志物，并且可以作为改善目前具有挑战性的软骨性骨肿瘤诊断的指标。此外，在原位异种移植小鼠模型中，两种 miRNA 的人工上调在体外和体内都产生了有效的肿瘤抑制作用。揭示了一种组合的计算机/测序方法FSCN1作为 miR-143/145 的直接靶标，其消耗表型类似于 miR-143/145 在体外的上调。最后，FSCN1是与侵袭性软骨肉瘤进展相关的恶性肿瘤促进因子。我们的研究结果强调了 miR-143/145/ FSCN1作为软骨肉瘤的重要参与者，并可能为特定的治疗干预选择开辟新的途径。© 2020 美国骨与矿物研究学会。