miR-374a/Myc axis modulates iron overload-induced production of ROS and the activation of hepatic stellate cells via TGF-β1 and IL-6

• Published in: Biochemical and biophysical research communications Vol. 515; no. 3; pp. 499 - 504
• Main Authors: Yuan, Qi, Zhang, Zheng, Hu, Xiaoxuan, Liao, Jinmao, Kuang, Jia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-07-2019
• Subjects: Hepatic fibrosis; Hepatic stellate cells (HSCs); Iron-overload; miR-374a/Myc axis; Reaction and active oxygen (ROS); Hepatic fibrosis; Reaction and active oxygen (ROS); Hepatic stellate cells (HSCs); Iron-overload; miR-374a/Myc axis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.05.152

The transformation of hepatic stellate cells (HSCs) to activated myofibroblasts plays a critical role in the progression of hepatic fibrosis, while iron-catalyzed production of free radical, including reaction and active oxygen (ROS), and activation and transformation of HSC into a myofibroblasts has been regarded as a major mechanism. In the present study, we attempted to investigate the mechanism of iron overload in hepatic fibrosis from the perspective of regulating HSC activation via oxidative stress and miR-374a/Myc axis. FAC stimulation significantly increased ROS production and TGF-β1 and IL-6 release dose-dependently in hepatocytes. miR-374a could target Myc, a co-transcription factor of both TGF-β1 and IL-6, to negatively regulate Myc expression; FAC stimulation significantly suppressed miR-374a expression, whereas the suppressive effect of FAC stimulation on miR-374a expression could be reversed by ROS inhibitor NAC, indicating that miR-374a could be modulated by iron overload-induced ROS. Via targeting Myc, miR-374a overexpression significantly reduced FAC-induced increases in TGF-β1 and IL-6 levels within L02 cells, whereas the effects of miR-374a overexpression were significantly attenuated via Myc overexpression. Finally, miR-374a overexpression attenuated FAC-induced activity of HSCs by decreasing α-SMA and Collagen I levels whereas Myc overexpression enhanced FAC-induced activity of HSCs by increasing α-SMA and Collagen I levels; the effects of miR-374a overexpression could also be significantly reversed by Myc overexpression, indicating that miR-374a suppresses the activation of HSCs by inhibiting Myc to reduce FAC-induced increases in TGF-β1 and IL-6 release. In conclusion, we demonstrate a novel mechanism of miR-374a/Myc axis modulating iron overload-induced production of ROS and the activation of HSCs via TGF-β1 and IL-6.
•MiR-374a levels were decreased in liver cells under FAC-induced iron overload.•miR-374a targets Myc to modulates L02 secretion of TGF-β1 and IL-6.•miR-374a/Myc inhibits iron-induced cytokine release to suppress the activation of hepatic stellate cells.