4th Department of Orthopaedic Surgery, Central Hospital affiliated to Shenyang Medical College, Shenyang, China.
School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China.
J Cell Mol Med. 2021 Jan;25(2):716-728. doi: 10.1111/jcmm.16121. Epub 2020 Nov 22.
Non-coding RNAs are closely associated with tumorigenesis in multiple malignant tumours, including osteosarcoma (OS). Long non-coding RNA Ewing sarcoma-associated transcript 1 (EWSAT1) plays a role in metastasis, and actin cytoskeletal changes in OS remain unclear. In the current study, we showed that EWSAT1 expression was up-regulated in OS and that an elevation in the EWSAT1 expression level was correlated with poor prognosis in patients with OS. Functionally, we showed that knockdown of EWSAT1 suppressed migration and induced actin stress fibre degradation in MNNG/HOS and 143B cells. Moreover, we found that ROCK1 was a key downstream effector in EWSAT1-mediated cell migration and actin stress fibre changes. Furthermore, we demonstrated that ROCK1 and EWSAT1 shared a similar microRNA response element of microRNA-24-3p (miR-24-3p). Moreover, we verified that miR-24-3p suppressed ROCK1 and its mediated migration and actin stress fibres change by direct targeting. EWSAT1 promoted ROCK1-mediated migration and actin stress fibre formation through miR-24-3p sponging. Lastly, through an in vivo study, we demonstrated that EWSAT1 promoted lung metastasis in OS. According to the above-mentioned results, we suggest that EWSAT1 acts as an oncogene and that EWSAT1/miR-24-3p/ROCK1 axial could be a new target in the treatment of OS.
非编码 RNA 与多种恶性肿瘤的肿瘤发生密切相关,包括骨肉瘤(OS)。长非编码 RNA Ewing 肉瘤相关转录本 1(EWSAT1)在 OS 的转移中发挥作用,但其在 OS 中的肌动蛋白细胞骨架变化仍不清楚。在本研究中,我们表明 EWSAT1 在 OS 中表达上调,并且 EWSAT1 表达水平的升高与 OS 患者的预后不良相关。功能上,我们表明 EWSAT1 的敲低抑制了 MNNG/HOS 和 143B 细胞的迁移,并诱导了肌动蛋白应力纤维降解。此外,我们发现 ROCK1 是 EWSAT1 介导的细胞迁移和肌动蛋白应力纤维变化的关键下游效应因子。此外,我们证明了 ROCK1 和 EWSAT1 共享 microRNA-24-3p(miR-24-3p)的相似 microRNA 反应元件。此外,我们通过直接靶向验证了 miR-24-3p 通过抑制 ROCK1 及其介导的迁移和肌动蛋白应力纤维变化来抑制 ROCK1。EWSAT1 通过 miR-24-3p 海绵作用促进 ROCK1 介导的迁移和肌动蛋白应力纤维形成。最后,通过体内研究,我们证明了 EWSAT1 促进了 OS 中的肺转移。根据上述结果,我们认为 EWSAT1 是一种癌基因,EWSAT1/miR-24-3p/ROCK1 轴可能是治疗 OS 的新靶点。