CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/β-catenin signaling pathway
CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/β-catenin signaling pathway
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DOI：
10.1007/s10735-020-09883-8
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发表时间：
2020-05-29
影响因子：
3.2
通讯作者：
Qu, Fangfei
中科院分区：
文献类型：
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作者：
Dong, Lin;Qu, Fangfei
化疗耐药的发生是骨肉瘤发病率高的重要原因。环状RNA（circRNA）参与调节癌症的化学抗性。Semaphorins 6D（SEMA6D）在许多癌症中异常表达。然而，circUBAP 2和SEMA 6D在OS的化疗耐药性中的作用仍不清楚。采用实时定量聚合酶链反应（qRT-PCR）检测circUBAP 2、SEMA6D和microRNA-506 - 3p（miR-506 - 3p）的表达水平。采用3-（4，5-二甲基-2-噻唑基）-2，5-二苯基-2-H-溴化四氮唑法检测细胞对顺铂的耐药性和增殖能力。进行蛋白质印迹分析以测量Wnt/β-连环蛋白信号传导途径生物标志物和SEMA6D的蛋白质水平。流式细胞术检测细胞凋亡，Transwell法检测细胞迁移和侵袭能力。此外，采用双荧光素酶报告基因检测miR-506 - 3p与circUBAP2或SEMA6D的相互作用。我们发现，circUBAP 2和SEMA6D的表达水平在顺铂耐药的OS组织和细胞中增加。敲低circUBAP 2可抑制顺铂耐药，沉默Wnt/beta-catenin信号通路，抑制细胞增殖、迁移和侵袭，促进细胞凋亡，而过表达SEMA6D可逆转上述作用。miR-506 - 3p可以被circUBAP 2吸收，并且可以靶向SEMA6D。miR-506 - 3p过表达对OS顺铂耐药进程的抑制作用可被SEMA6D过表达逆转，而miR-506 - 3p抑制剂也可逆转circUBAP 2沉默对OS顺铂耐药进程的抑制作用。综上所述，CircUBAP2和SEMA6D通过miR-506 - 3p在卵巢癌顺铂耐药过程中发挥了积极作用，为研究卵巢癌顺铂耐药的对策提供了新的思路。
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/beta-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/beta-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.