Archives of Toxicology

, Volume 93, Issue 11, pp 3261–3276 | Cite as

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

  • Yanzhuo Liu
  • Chenfan Duan
  • Wen Liu
  • Xuewei Chen
  • Yang Wang
  • Xiaoxiao Liu
  • Jiang Yue
  • Jing Yang
  • Xiaoyang ZhouEmail author
Organ Toxicity and Mechanisms


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 μM) 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.


Doxorubicin Let-7f-2-3p LncRNA NEAT1 XPO1 HAX-1 Cardiotoxicity 



Creatine kinase-myocardial bound


Creatine phosphokinase




Gene Expression Omnibus


Hematopoietic-substrate-1 associated protein X-1


Lactate dehydrogenase




Exportin 1



This work was partly supported by the National Natural Science Foundation of China [Grant Nos. 81970331 and 81370337 (to Xiaoyang Zhou) and 81872443 (to Jing Yang)], and Medical Science Advancement Program (Basic Medical Science) of Wuhan University, Grant No. TFJC 2018003.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2019_2586_MOESM1_ESM.docx (725 kb)
Supplementary material 1 (DOCX 724 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiology, Renmin HospitalWuhan UniversityWuhanChina
  2. 2.Department of Pharmacology and Hubei Province Key Laboratory of Allergy and Immune-related Diseases, School of Basic Medical SciencesWuhan UniversityWuhanChina
  3. 3.Department of Laboratory Medicine, Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanChina

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