Multiple myeloma is a frequent hematologic malignancy. Bortezomib is the first-line drug for multiple myeloma chemotherapy. The present study aimed to investigate the potential role and mechanism of circular RNA chaperonin containing TCP1 subunit 3 (circ-CCT3) in bortezomib resistance of multiple myeloma. The levels of circ-CCT3, microRNA-223-3p (miR-223-3p), and bromodomain-containing 4 (BRD4) were detected by quantitative real-time PCR or western blot. Cell Counting Kit-8 (CCK-8) method was used to measure the half-inhibitory concentration of bortezomib and cell viability. Cell cycle distribution, apoptosis, proliferation and migration were determined by flow cytometry, 5-ethynyl-2'-deoxyuridine, and wound healing assay. The levels of relevant proteins were checked via western blot. The binding association between miR-223-3p and circ-CCT3/BRD4 was validated via a dual-luciferase reporter assay. Circ-CCT3 and BRD4 were upregulated, while miR-223-3p was downregulated in bortezomib-resistant multiple myeloma patients and cells. Silencing of circ-CCT3 enhanced the sensitivity of bortezomib-resistant multiple myeloma cells to bortezomib. Circ-CCT3 knockdown weakened bortezomib resistance via modulating miR-223-3p. Moreover, miR-223-3p increased bortezomib sensitivity by inhibiting BRD4. Downregulation of circ-CCT3 attenuated bortezomib resistance of multiple myeloma via regulating miR-223-3p/BRD4 pathway, which provided a new potential target for multiple myeloma chemoresistance.

中文翻译：

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环状 RNA circ-CCT3 通过调节 miR-223-3p/BRD4 轴促进多发性骨髓瘤中的硼替佐米耐药。

多发性骨髓瘤是一种常见的血液系统恶性肿瘤。硼替佐米是多发性骨髓瘤化疗的一线药物。本研究旨在探讨含有TCP1亚基3（circ-CCT3）的环状RNA伴侣蛋白在多发性骨髓瘤硼替佐米耐药中的潜在作用和机制。通过实时定量 PCR 或蛋白质印迹检测 circ-CCT3、microRNA-223-3p (miR-223-3p) 和 bromodomain- contains 4 (BRD4) 的水平。采用细胞计数试剂盒-8（CCK-8）法测定硼替佐米的半抑浓度和细胞活力。通过流式细胞术、5-乙炔基-2'-脱氧尿苷和伤口愈合测定来测定细胞周期分布、凋亡、增殖和迁移。通过蛋白质印迹检查相关蛋白质的水平。通过双荧光素酶报告基因测定验证了 miR-223-3p 和 circ-CCT3/BRD4 之间的结合关联。在硼替佐米耐药的多发性骨髓瘤患者和细胞中，Circ-CCT3 和 BRD4 上调，而 miR-223-3p 下调。circ-CCT3的沉默增强了硼替佐米耐药的多发性骨髓瘤细胞对硼替佐米的敏感性。Circ-CCT3 敲低通过调节 miR-223-3p 减弱硼替佐米耐药性。此外，miR-223-3p 通过抑制 BRD4 增加硼替佐米的敏感性。下调circ-CCT3通过调节miR-223-3p/BRD4通路减弱多发性骨髓瘤的硼替佐米耐药，这为多发性骨髓瘤化疗耐药提供了新的潜在靶点。