The occurrence of chemo-resistance is an essential reason for the high morbidity of osteosarcoma (OS) patients. Circular RNAs (circRNAs) have been involved in the regulation of chemo-resistance in cancers. Semaphorins 6D (SEMA6D) is abnormally expressed in many cancers. However, the roles of circUBAP2 and SEMA6D in the chemo-resistance of OS are still unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circUBAP2, SEMA6D and microRNA-506-3p (miR-506-3p). The cisplatin resistance and proliferation of cells were evaluated by 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay. Western blot analysis was performed to measure the protein levels of Wnt/β-catenin signaling pathway biomarkers and SEMA6D. Also, the apoptosis, migration and invasion of cells were assessed by Flow cytometry and Transwell assays, respectively. Besides, Dual-luciferase reporter assay was used to verify the interaction between miR-506-3p and circUBAP2 or SEMA6D. We found that the expression levels of circUBAP2 and SEMA6D were increased in cisplatin-resistant OS tissues and cells. Knockdown of circUBAP2 inhibited the cisplatin resistance, silenced Wnt/β-catenin signaling pathway, hindered cell proliferation, migration and invasion, and promoted apoptosis in cisplatin-resistant OS cells, all of which could be reversed by overexpression of SEMA6D. MiR-506-3p could be sponged by circUBAP2 and could target SEMA6D. The suppression of miR-506-3p overexpression on the progression of OS cisplatin resistance could be reversed by SEMA6D overexpression, while miR-506-3p inhibitor also could invert the inhibitory effect of circUBAP2 silencing on the progression of OS cisplatin resistance. In conclusion, CircUBAP2 and SEMA6D played active roles in the progression of OS cisplatin resistance through miR-506-3p, which might provide some new ideas for studying the countermeasures of OS resistance.

中文翻译：

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CircUBAP2 通过激活 Wnt/β-连环蛋白信号通路海绵化 miR-506-3p，促进 SEMA6D 表达，从而增强骨肉瘤的顺铂耐药性。

化疗耐药性的发生是骨肉瘤 (OS) 患者高发病率的重要原因。环状 RNA (circRNA) 参与了癌症化疗耐药性的调节。Semaphorins 6D (SEMA6D) 在许多癌症中异常表达。然而，circUBAP2 和 SEMA6D 在 OS 化疗耐药中的作用仍不清楚。使用定量实时聚合酶链反应（qRT-PCR）检测circUBAP2、SEMA6D和microRNA-506-3p（miR-506-3p）的表达水平。3-(4, 5-二甲基-2噻唑基)-2, 5-二苯基-2- H评价细胞的顺铂耐药性和增殖能力-四唑溴化物测定。进行蛋白质印迹分析以测量 Wnt/β-连环蛋白信号通路生物标志物和 SEMA6D 的蛋白质水平。此外，分别通过流式细胞术和 Transwell 测定评估细胞的凋亡、迁移和侵袭。此外，双荧光素酶报告基因检测用于验证 miR-506-3p 与 circUBAP2 或 SEMA6D 之间的相互作用。我们发现 circUBAP2 和 SEMA6D 的表达水平在顺铂耐药的 OS 组织和细胞中增加。敲低 circUBAP2 可抑制顺铂耐药，沉默 Wnt/β-catenin 信号通路，阻碍细胞增殖、迁移和侵袭，促进顺铂耐药 OS 细胞凋亡，所有这些均可通过 SEMA6D 的过表达逆转。MiR-506-3p 可以被 circUBAP2 吸收并可以靶向 SEMA6D。SEMA6D 过表达可以逆转 miR-506-3p 过表达对 OS 顺铂耐药进展的抑制，而 miR-506-3p 抑制剂也可以逆转 circUBAP2 沉默对 OS 顺铂耐药进展的抑制作用。总之，CircUBAP2 和 SEMA6D 通过 miR-506-3p 在 OS 顺铂耐药的进展中发挥了积极作用，这可能为研究 OS 耐药的对策提供一些新思路。