MicroRNA-31-5p attenuates doxorubicin-induced cardiotoxicity via quaking and circular RNA Pan3
MicroRNA-31-5p attenuates doxorubicin-induced cardiotoxicity via quaking and circular RNA Pan3
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DOI：
10.1016/j.yjmcc.2020.02.009
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发表时间：
2020-03-01
影响因子：
5
通讯作者：
Wang, Jianxun
中科院分区：
文献类型：
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作者：
Ji, Xiaoyu;Ding, Wei;Wang, Jianxun
目的：阿霉素（DOX）是一种广谱的抗肿瘤药物，但具有相当的心脏毒性。DOX可通过调节多条信号通路诱导心肌细胞凋亡。更好地了解DOX的心脏毒性的潜在机制，将提高其临床应用，并有助于避免心力衰竭patient.Methods和结果：在培养的心肌细胞和小鼠的DOX心脏毒性模型。TUNEL法和caspase 3/7活性测定法检测细胞凋亡。通过免疫印迹检测Quaking（QKI）表达;通过qRT-PCR测定microRNA-31 - 5p和环状RNA（circRNA）水平。进行荧光素酶报告基因测定以验证miR-31 - 5p靶标。我们发现DOX处理上调了培养的心肌细胞和小鼠心脏组织中miR-31 - 5p的表达。miR-31 - 5p的沉默可显著减轻DOX诱导的心肌细胞凋亡。进一步的分析表明QKI是miR-31 - 5p的直接靶点，据报道miR-31 - 5p影响一系列细胞类型中的circRNA表达。我们发现，在DOX处理后，circPan3在心肌细胞中特异性下调。结论：miR-31 - 5p、QKI和circPan3在心肌细胞凋亡过程中存在一定的相关性。miR-31 - 5p通过直接抑制QKI而作为circPan3的负调节剂，这可能是DOX诱导的心脏毒性的潜在治疗靶点和策略。
Aims: Doxorubicin (DOX) is a broad-spectrum anticancer drug with considerable cardiotoxicity. DOX can induce myocardial apoptosis by modulating multiple signalling pathways. A better understanding of the underlying mechanism of DOX's cardiotoxicity will improve its clinical application and help avoid heart failure in patients.Methods and results: Models of DOX cardiotoxicity in cultured cardiomyocytes and mice were used. Cell death was determined by TUNEL and caspase 3/7 activity assay. Quaking (QKI) expression was detected by immunoblotting; microRNA-31-5p and circular RNA (circRNA) levels were determined by qRT-PCR. Luciferase reporter assays were performed to validate the miR-31-5p target. We found that DOX treatment upregulated miR-31-5p expression both in cultured cardiomyocytes and in mouse heart tissue. Silencing of miR-31-5p significantly alleviated the myocardial apoptosis induced by DOX treatment both in vivo and in vitro. Further analysis indicated QKI as a direct target of miR-31-5p, which has been reported to influence circRNA expression in a series of cell types. We found that circPan3 was specifically downregulated in cardiomyocytes upon DOX treatment. We further confirmed that the downregulation of circPan3 was due to the silencing of QKI by miR-31-5p.Conclusions: Our data reveal links among miR-31-5p, QKI and circPan3 in the apoptotic programme of cardiomyocytes. MiR-31-5p acted as a negative regulator of circPan3 by directly suppressing QKI, which may be a potential therapeutic target and strategy for DOX-induced cardiotoxicity.