Changyi people's hospital, Department of spinal surgery, 261300 Changyi, Weifang city, Shandong province, China.
Changyi people's hospital, Department of anesthesiology, 261300 Changyi, Weifang city, Shandong province, China.
Bull Cancer. 2021 Jun;108(6):596-604. doi: 10.1016/j.bulcan.2021.01.006. Epub 2021 Apr 15.
Osteosarcoma (OS) is a human malignancy, which primarily affects the long bones and occurs in children and adolescent. Although advanced clinical approaches and the addition of neoadjuvant chemotherapy improved 5-year survival of OS patients, a large fraction of them developed chemoresistance. Thus, due to the high morbidity and mortality of OS, it is urgent to investigate effectively molecular targets against chemoresistant osteosarcoma. In this study, we aimed to evaluate the functions of miR-27a-3p in the Taxol sensitivity of osteosarcoma. From fifty-paired OS tumour tissues and adjacent normal bone tissues, we detected significantly upregulated miR-27a-3p expressions in osteosarcoma. In addition, expression of miR-27a-3p was remarkedly elevated in OS cancer cell lines compared with normal osteoblast cells, hFOB1.19. Blocking miR-27a-3p effectively suppressed OS cell growth and sensitised OS cells to Taxol. miRNA target prediction indicated Fbxw7 was a potential target of miR-27a-3p. We demonstrated Fbxw7 functioned as a tumour suppressor in osteosarcoma. Overexpression of miR-27a-3p significantly suppressed Fbxw7 protein expression in OS cells. The direct binding between miR-27a-3p and Fbxw7 3'UTR was validated by luciferase assay. Particularly, results from rescue experiments by inhibiting Fbxw7 expressions in miR-23a-3p-blocked OS cells demonstrated the miR-27a-3p-mediated Taxol resistance was through direct targeting Fbxw7. In summary, our findings report a new molecular mechanism for the miR-27a-3p-mediated Taxol resistance via targeting tumour suppressor, Fbxw7 in osteosarcoma. This study potentiates a miRNA-based therapeutic approach against Taxol resistant osteosarcoma.
骨肉瘤（OS）是一种人类恶性肿瘤，主要影响长骨，发生于儿童和青少年。尽管先进的临床方法和新辅助化疗的加入提高了 OS 患者的 5 年生存率，但他们中的很大一部分仍发生了化疗耐药。因此，由于 OS 的高发病率和死亡率，迫切需要研究针对化疗耐药骨肉瘤的有效分子靶点。在这项研究中，我们旨在评估 miR-27a-3p 在紫杉醇治疗骨肉瘤中的作用。从 50 对骨肉瘤肿瘤组织和相邻正常骨组织中，我们检测到骨肉瘤中 miR-27a-3p 的表达显著上调。此外，与正常成骨细胞 hFOB1.19 相比，miR-27a-3p 在 OS 癌细胞系中的表达显著升高。抑制 miR-27a-3p 可有效抑制 OS 细胞的生长并使 OS 细胞对紫杉醇敏感。miRNA 靶标预测表明 Fbxw7 是 miR-27a-3p 的一个潜在靶标。我们证明 Fbxw7 在骨肉瘤中起肿瘤抑制因子的作用。miR-27a-3p 的过表达显著抑制了 OS 细胞中 Fbxw7 蛋白的表达。荧光素酶测定验证了 miR-27a-3p 与 Fbxw7 3'UTR 之间的直接结合。特别是，在 miR-27a-3p 阻断的 OS 细胞中抑制 Fbxw7 表达的挽救实验结果表明，miR-27a-3p 介导的紫杉醇耐药是通过直接靶向肿瘤抑制因子 Fbxw7 实现的。总之，我们的研究结果报告了 miR-27a-3p 通过靶向肿瘤抑制因子 Fbxw7 介导紫杉醇耐药的新分子机制。这项研究为基于 miRNA 的治疗方法提供了一种对抗紫杉醇耐药骨肉瘤的策略。
