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Published on: June 15, 2018
MicroRNA-31-5p attenuates doxorubicin-induced cardiotoxicity via quaking and circular RNA Pan3
Xiaoyu Ji1, Wei Ding2, Tao Xu3
1School of Basic Medicine, Qingdao University, Qingdao, China; Institute for Translational Medicine, Qingdao University, Qingdao 266021, China.
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.
Insights
Doxorubicin (DOX) induces heart damage by increasing miR-31-5p, which suppresses Quaking (QKI) and downregulates circPan3, leading to myocardial apoptosis. Targeting this pathway may prevent DOX cardiotoxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiology
Background:
- Doxorubicin (DOX) is a potent anticancer agent.
- DOX causes significant cardiotoxicity, leading to heart failure.
- Understanding DOX-induced myocardial apoptosis mechanisms is crucial for clinical management.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying DOX-induced cardiotoxicity.
- To investigate the role of microRNA-31-5p (miR-31-5p) and Quaking (QKI) in DOX cardiotoxicity.
- To identify potential therapeutic targets for mitigating DOX-induced heart damage.
Main Methods:
- Utilized cell and mouse models of DOX cardiotoxicity.
- Assessed cell death using TUNEL and caspase 3/7 assays.
- Quantified miR-31-5p, circular RNA (circPan3), and QKI expression via qRT-PCR and immunoblotting.
- Validated miR-31-5p targets using luciferase reporter assays.
Main Results:
- DOX treatment upregulated miR-31-5p expression in cardiomyocytes and heart tissue.
- Silencing miR-31-5p reduced DOX-induced myocardial apoptosis in vitro and in vivo.
- QKI was identified as a direct target of miR-31-5p.
- circPan3 expression was downregulated by DOX, mediated by miR-31-5p-induced QKI suppression.
Conclusions:
- MiR-31-5p, QKI, and circPan3 are interconnected in DOX-induced cardiomyocyte apoptosis.
- MiR-31-5p negatively regulates circPan3 by suppressing QKI.
- This pathway represents a potential therapeutic target for DOX cardiotoxicity.
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