Several microRNAs (miRNAs) and circular RNAs (circRNAs) were reported to be involved in the Docetaxel (DTX) chemoresistance of cancer treatment, but the underlying mechanisms remain to be explored. In this study, we established cellular and animal models respectively to study the effect and underlying molecular mechanisms of the dysregulation of circRNA_0006404 and circRNA_0000735 in tumor response to DTX treatment. Quantitative real-time PCR was performed to measure the expression of circRNA_0006404, miR-346, circRNA_0000735, miR-526b, Dickkopf-related protein 3 (DKK3), and Dickkopf-related protein 4 (DKK4) mRNA. The expression of circRNA_0006404 and circRNA_0000735 was remarkably suppressed and activated in DTX-treated SKOV3-R cell lines, respectively. As revealed by luciferase assays, circRNA_0006404 and circRNA_0000735 was found to be respectively targeted by miR-346 and miR-526b, while DKK3 and DKK4 were respectively targeted by miR-346 and miR-526b. Moreover, the expression of DKK3 and DKK4, which were targets of miR-346 and miR-526b, respectively, was significantly altered along with the expression of p-GP. Furthermore, circ_0006404 shRNA and circRNA_0000735 shRNA showed remarkable efficiency in stimulating the expression of circRNA_0006404, miR-346, DKK3, circRNA_0000735, miR-526b, DKK4, and p-GP in cellular and animal models. Accordingly, the cell apoptosis and proliferation were apparently changed by circ_0006404 shRNA and circRNA_0000735 shRNA in both cellular and animal models. In summary, our study found the involvement of the circRNA_0006404/miR-346/DKK3/p-GP and circRNA_0000735/miR-546b/DKK4/p-GP axis in the tumor response to DTX. Both the up-regulation of circRNA_0006404 and down-regulation of circRNA_0000735 could inhibit the expression of p-GP in vivo and ex vivo, leading to the suppressed tumor response to DTX treatment.

据报道，几种 microRNA (miRNA) 和环状 RNA (circRNA) 与癌症治疗的多西紫杉醇 (DTX) 化学抗性有关，但其潜在机制仍有待探索。在这项研究中，我们分别建立了细胞和动物模型，以研究 circRNA_0006404 和 circRNA_0000735 失调在 DTX 治疗肿瘤反应中的影响和潜在的分子机制。进行定量实时 PCR 以测量 circRNA_0006404、miR-346、circRNA_0000735、miR-526b、Dickkopf 相关蛋白 3 (DKK3) 和 Dickkopf 相关蛋白 4 (DKK4) mRNA 的表达。在 DTX 处理的 SKOV3-R 细胞系中，circRNA_0006404 和 circRNA_0000735 的表达分别被显着抑制和激活。正如萤光素酶测定所揭示的，发现circRNA_0006404和circRNA_0000735分别被miR-346和miR-526b靶向，而DKK3和DKK4分别被miR-346和miR-526b靶向。此外，分别作为 miR-346 和 miR-526b 的靶标的 DKK3 和 DKK4 的表达随着 p-GP 的表达而显着改变。此外，circ_0006404 shRNA 和 circRNA_0000735 shRNA 在刺激细胞和动物模型中 circRNA_0006404、miR-346、DKK3、circRNA_0000735、miR-526b、DKK4 和 p-GP 的表达方面表现出显着的效率。因此，在细胞和动物模型中，circ_0006404 shRNA 和 circRNA_0000735 shRNA 明显改变了细胞凋亡和增殖。总之，我们的研究发现 circRNA_0006404/miR-346/DKK3/p-GP 和 circRNA_0000735/miR-546b/DKK4/p-GP 轴参与了肿瘤对 DTX 的反应。circRNA_0006404的上调和circRNA_0000735的下调都可以在体内和离体抑制p-GP的表达，从而抑制肿瘤对DTX治疗的反应。