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MicroRNA-128-3p aggravates doxorubicin-induced liver injury by promoting oxidative stress via targeting Sirtuin-1.

Abstract：

:As one classic anticancer drug, clinical application of Doxorubicin (Dox) is limited due to its side effects. In our previous work, we have investigated the drug targets to treat Dox-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. In this paper, the mechanisms and new drug-target associated with Dox-induced hepatotoxicity were explored. The results showed that Dox markedly inhibited cell viability and cellular respiration, induced cell morphologic change and increased ROS level. Moreover, Dox increased ALT and AST levels, caused pathological damage, increased MDA level and decreased SOD level in mice. Mechanism investigation showed that Dox markedly up-regulated the expression level of miR-128-3p, down-regulated Sirt1 expression level and affected the protein levels of Nrf2, Keap1, Sirt3, NQO1 and HO-1 to cause oxidative stress in liver. Furthermore, double-luciferase reporter assay, and co-transfection test showed that miR-128-3p directly targeted Sirt1. In addition, miR-128-3p mimics in AML-12 cells enhanced Dox-induced oxidative damage via inhibiting cellular respiration, increasing ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p mimic + Dox group were decreased compared with Dox group. Transfection of miR-128-3p inhibitor weakened Dox-induced oxidative damage via increasing cellular respiration, suppressing cellular ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p inhibitor + Dox group were increased compared with Dox group. In mice, Dox-induced liver damage was deteriorated by miR-128-3p agomir via increasing the levels of ALT, AST, MDA, and down-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. While, miR-128-3p antagomir alleviated liver injury via decreasing the levels of ALT, AST, MDA, and up-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. Our data showed that miRNA-128-3p aggravated Dox-induced liver injury by promoting oxidative stress via targeting Sirt1, which should be considered as one new drug target to treat Dox-induced liver injury.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Zhao X,Jin Y,Li L,Xu L,Tang Z,Qi Y,Yin L,Peng J

doi

10.1016/j.phrs.2019.104276

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

104276

eissn

1043-6618

issn

1096-1186

pii

S1043-6618(19)30266-X

journal_volume

146

pub_type

杂志文章

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MicroRNA-128-3p aggravates doxorubicin-induced liver injury by promoting oxidative stress via targeting Sirtuin-1.