Upregulation of let-7f-2-3p by long noncoding RNA NEAT1 inhibits XPO1-mediated HAX-1 nuclear export in both in vitro and in vivo rodent models of doxorubicin-induced cardiotoxicity
Upregulation of let-7f-2-3p by long noncoding RNA NEAT1 inhibits XPO1-mediated HAX-1 nuclear export in both in vitro and in vivo rodent models of doxorubicin-induced cardiotoxicity
复制标题
在多柔比星诱导的心脏毒性的体外和体内啮齿动物模型中，长非编码 RNA NEAT1 上调 let-7f-2-3p 抑制 XPO1 介导的 HAX-1 核输出
DOI：
10.1007/s00204-019-02586-4
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发表时间：
2019-11-01
影响因子：
6.1
通讯作者：
Zhou, Xiaoyang
中科院分区：
文献类型：
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作者：
Liu, Yanzhuo;Duan, Chenfan;Zhou, Xiaoyang
多柔比星（Dox）由于其不良的副作用，特别是心脏毒性而限制了其临床应用。一些microRNA（miRNAs）如microRNA-140- 5 p和miR-23 a加重了Dox诱导的心脏毒性。在这里，我们证明了长链非编码RNA（lncRNA）NEAT 1上调miRNA let-7 f-2- 3 p可以抑制输出蛋白-1（XPO 1）介导的Dox诱导的心脏毒性中造血底物-1相关蛋白X-1（HAX-1）的核输出。用Dox（1 μ M）处理H9 c2细胞6小时抑制HAX-1核输出并降低XPO 1表达。XPO 1的过表达显著减弱了Dox诱导的心肌酶（肌酸磷酸激酶，肌酸激酶MB和乳酸脱氢酶）的泄漏和心肌细胞凋亡，增加HAX-1核输出。从Dox或载体处理的心肌细胞中选择差异表达的miRNA，包括let-7 f-2- 3 p。TargetScan和荧光素酶检测显示let-7 f-2- 3 p靶向XPO 1 3' UTR。let-7 f-2- 3 p的抑制通过抑制XPO 1介导的HAX-1核输出而减少了Dox诱导的心脏毒性和细胞凋亡，而let-7 f-2- 3 p的过表达加重了这些作用。此外，lncRNA NEAT 1被鉴定为抑制let-7 f-2- 3 p表达的内源性海绵RNA。过表达lncRNA NEAT 1可抑制Dox引起的let-7 f-2- 3 p表达增加，从而减轻心脏毒性。let-7 f-2- 3 p的功能丧失增加了XPO 1介导的HAX-1核输出，并减少了Dox（20 mg/kg）治疗大鼠的心肌损伤。重要的是，let-7 f-2- 3 p在小鼠中的抑制减轻了Dox诱导的心脏毒性并保持了抗肿瘤功效。总之，lncRNA NEAT 1调节的let-7 f-2- 3 p通过抑制XPO 1介导的HAX-1核输出来减轻Dox诱导的心脏毒性，并且可能作为针对Dox诱导的心脏毒性的潜在治疗靶点。
Clinical application of doxorubicin (Dox) is limited due to its undesirable side effects, especially cardiotoxicity. Several microRNAs (miRNAs) such as microRNA-140-5p and miR-23a aggravate Dox-induced cardiotoxicity. Here we demonstrate that upregulation of miRNA let-7f-2-3p by long noncoding RNA (lncRNA) NEAT1 inhibits exportin-1 (XPO1)-mediated nuclear export of hematopoietic-substrate-1 associated protein X-1 (HAX-1) in Dox-induced cardiotoxicity. Treatment of the H9c2 cells with the Dox (1 mu M) for 6 h inhibited HAX-1 nuclear export and decreased XPO1 expression. Overexpression of XPO1 significantly attenuated the Dox-induced leakage of myocardial enzymes (creatine phosphokinase, creatine kinase-MB and lactate dehydrogenase) and cardiomyocyte apoptosis with the increased HAX-1 nuclear export. Differentially expressed miRNAs including let-7f-2-3p were selected from the Dox or vehicle-treated cardiomyocytes. TargetScan and luciferase assay showed that let-7f-2-3p targeted XPO1 3' UTR. Inhibition of let-7f-2-3p reduced Dox-induced cardiotoxicity and apoptosis by inhibiting XPO1-mediated HAX-1 nuclear export, whereas let-7f-2-3p overexpression aggravated these effects. In addition, lncRNA NEAT1 was identified as an endogenous sponge RNA to repress let-7f-2-3p expression. Overexpression of lncRNA NEAT1 abolished the increased let-7f-2-3p expression by Dox, and thereby attenuated cardiotoxicity. The loss function of let-7f-2-3p increased XPO1-mediated HAX-1 nuclear export and reduced myocardial injury in Dox (20 mg/kg)-treated rats. Importantly, let-7f-2-3p inhibition in mice alleviated Dox-induced cardiotoxicity and preserved the antitumor efficacy. Together, let-7f-2-3p regulated by lncRNA NEAT1 aggravates Dox-induced cardiotoxicity through inhibiting XPO1-mediated HAX-1 nuclear export, and may serve as a potential therapeutic target against Dox-induced cardiotoxicity.