circ_0080145 通过调控 miR-326/PPFIA1 轴增强慢性髓性白血病的伊马替尼耐药性

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cancer Biotherapy and Radiopharmaceuticals Pub Date : 2024-09-01 Epub Date: 2020-06-27 DOI:10.1089/cbr.2020.3600
Hong Che, Hong Ding, Xizhen Jia
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引用次数: 0

摘要

背景:包括慢性髓性白血病(CML)在内的恶性肿瘤患者化疗失败的原因通常归咎于获得性多药耐药性。在这项研究中,作者调查了环状 RNA 0080145(circ_0080145)在 CML 的伊马替尼(IM)耐药性中的作用。材料与方法:应用定量实时聚合酶链反应测量circ_0080145、microRNA-326(miR-326)和PTPRF相互作用蛋白α1(PPFIA1)mRNA的表达。3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-溴化四氮唑(MTT)测定法用于确定 IM 的半最大抑制浓度(IC50)和细胞增殖。流式细胞术分析用于评估细胞凋亡。使用特定试剂盒检测葡萄糖摄取和乳酸生成水平。蛋白质水平则通过 Western 印迹分析法检测。通过双荧光素酶报告实验验证了 miR-326 与 circ_0080145 或 PPFIA1 之间的靶向关系。建立了小鼠异种移植模型来研究 circ_0080145 在体内的作用。结果:circ_0080145在IM耐药的CML患者和细胞中上调,沉默circ_0080145可抑制IM耐药、细胞生长和糖酵解,并诱导体外IM耐药CML细胞凋亡。miR-326是circ_0080145的靶标,抑制miR-326可恢复circ_0080145沉默对细胞进展和IM耐药的影响。此外,PPFIA1也是miR-326的靶基因。在IM耐药的CML细胞中,PPFIA1的过表达取消了miR-326在IM耐药、细胞生长和糖酵解中的抑制作用以及在细胞凋亡中的促进作用。结论:circ_0080145通过调节miR-326/PPFIA1轴导致IM耐药,这可能为CML治疗提供了一条新途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
circ_0080145 Enhances Imatinib Resistance of Chronic Myeloid Leukemia by Regulating miR-326/PPFIA1 Axis.

Background: Acquired multidrug resistance is often blamed for the failure of chemotherapy in patients with malignant tumors, including chronic myeloid leukemia (CML). In this study, the authors investigated the role of circular RNA 0080145 (circ_0080145) in imatinib (IM) resistance of CML. Materials and Methods: Quantitative real-time polymerase chain reaction was applied to measure the expression of circ_0080145, microRNA-326 (miR-326), and PTPRF interacting protein alpha 1 (PPFIA1) mRNA. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the half maximal inhibitory concentration (IC50) of IM and cell proliferation. Flow cytometry analysis was utilized to assess cell apoptosis. The levels of glucose uptake and lactate production were examined using specific kits. Protein levels were detected through Western blot assay. The targeting relationship between miR-326 and circ_0080145 or PPFIA1 was verified by dual-luciferase reporter assay. The murine xenograft model was constructed to investigate the effect of circ_0080145 in vivo. Results: circ_0080145 was upregulated in IM-resistant CML patients and cells. circ_0080145 silencing suppressed IM resistance, cell growth, and glycolysis and induced apoptosis in IM-resistant CML cells in vitro. Moreover, circ_0080145 knockdown blocked tumor growth and IM resistance in vivo. miR-326 was a target of circ_0080145, and miR-326 inhibition restored the effects of circ_0080145 silencing on cell progression and IM resistance. In addition, PPFIA1 was a target gene of miR-326. The suppressive roles in IM resistance, cell growth and glycolysis, and the promotional role in apoptosis mediated by miR-326 were abolished by PPFIA1 overexpression in IM-resistant CML cells. Conclusion: circ_0080145 contributes to IM resistance via modulating miR-326/PPFIA1 axis, which might provide a novel avenue for CML therapy.

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来源期刊
CiteScore
7.80
自引率
2.90%
发文量
87
审稿时长
3 months
期刊介绍: Cancer Biotherapy and Radiopharmaceuticals is the established peer-reviewed journal, with over 25 years of cutting-edge content on innovative therapeutic investigations to ultimately improve cancer management. It is the only journal with the specific focus of cancer biotherapy and is inclusive of monoclonal antibodies, cytokine therapy, cancer gene therapy, cell-based therapies, and other forms of immunotherapies. The Journal includes extensive reporting on advancements in radioimmunotherapy, and the use of radiopharmaceuticals and radiolabeled peptides for the development of new cancer treatments.
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