MicroRNA-31-5p attenuates doxorubicin-induced cardiotoxicity via quaking and circular RNA Pan3.

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.

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