Circ_0025033 缺失通过调节 miR-532-3p/FOXM1 网络抑制紫杉醇耐药卵巢癌细胞的紫杉醇耐药性和恶性发展。
Circ_0025033 deficiency suppresses paclitaxel resistance and malignant development of paclitaxel-resistant ovarian cancer cells by modulating the miR-532-3p/FOXM1 network.
机构信息
Department of Obstetrics and Gynecology, First Affiliated Hospital of Jinan University, Guangzhou, P. R. China.
Department of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, P. R. China.
出版信息
Immunopharmacol Immunotoxicol. 2022 Apr;44(2):275-286. doi: 10.1080/08923973.2022.2038194. Epub 2022 Feb 24.
BACKGROUND
Ovarian cancer (OC) is the main cause of cancer-related death in women, and drug resistance is a leading cause of treatment failure. Recently, the involvement of circular RNAs (circRNAs) in cancer progression has become an area of increased investigation. The objective of this study is to uncover the function and regulatory mechanism of circ_0025033 in paclitaxel (PTX)-resistant OC cells.
METHODS
The expression of circ_0025033, FOXM1 and miR-532-3p was investigated using quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expression of FOXM1 was quantified by western blot. Cell biological functions, including cell viability, migration/invasion and apoptosis, were explored using 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays, transwell assays and flow cytometry assays. The interaction between miR-532-3p and circ_0025033 or FOXM1 predicted by bioinformatics analysis was validated by pull-down assay and dual-luciferase reporter assay. Exosomes were isolated to determine the further function of circ_0025033.
RESULT
Circ_0025033 and FOXM1 were highly expressed, while miR-532-3p was poorly expressed in OC tissues and cells, and the expression pattern was greater in PTX-resistant OC cells. Circ_0025033 knockdown lessened PTX resistance, suppressed migration/invasion and promoted apoptosis of PTX-resistant cells. With respect to mechanism, circ_0025033 upregulated the expression of FOXM1 by targeting miR-532-3p, and circ_0025033 knockdown blocked the malignant activities of PTX-resistant OC cells by enriching miR-532-3p and suppressing FOXM1. Exosomes derived from PTX-resistant cells with circ_0025033 knockdown also could repress the malignant actions of PTX-resistant OC cells.
CONCLUSION
Circ_0025033 downregulation impaired PTX resistance and malignant activities of PTX-resistant OC cells by regulating the miR-532-3p/FOXM1 network.
背景
卵巢癌（OC）是女性癌症相关死亡的主要原因，而耐药性是治疗失败的主要原因。最近，环状 RNA（circRNA）在癌症进展中的作用成为研究的热点。本研究旨在揭示 circ_0025033 在紫杉醇（PTX）耐药 OC 细胞中的功能和调控机制。
方法
采用实时定量聚合酶链反应（qRT-PCR）检测 circ_0025033、FOXM1 和 miR-532-3p 的表达，采用 Western blot 定量检测 FOXM1 的蛋白表达。采用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）试验、Transwell 试验和流式细胞术试验研究细胞生物学功能，包括细胞活力、迁移/侵袭和凋亡。通过下拉试验和双荧光素酶报告基因试验验证生物信息学分析预测的 miR-532-3p 与 circ_0025033 或 FOXM1 之间的相互作用。分离外泌体以确定 circ_0025033 的进一步功能。
结果
circ_0025033 和 FOXM1 在 OC 组织和细胞中高表达，而 miR-532-3p 表达水平较低，且在 PTX 耐药 OC 细胞中表达模式更为显著。circ_0025033 敲低降低了 PTX 耐药性，抑制了 PTX 耐药细胞的迁移/侵袭并促进了凋亡。就机制而言，circ_0025033 通过靶向 miR-532-3p 上调 FOXM1 的表达，而 circ_0025033 敲低通过富集 miR-532-3p 和抑制 FOXM1 阻断 PTX 耐药 OC 细胞的恶性活动。来自 circ_0025033 敲低的 PTX 耐药细胞的外泌体也可以抑制 PTX 耐药 OC 细胞的恶性作用。
结论
circ_0025033 下调通过调节 miR-532-3p/FOXM1 网络损害 PTX 耐药和 PTX 耐药 OC 细胞的恶性活动。
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