Biochemical and Biophysical Research Communications, Vol.515, No.3, 499-504, 2019
miR-374a/Myc axis modulates iron overload-induced production of ROS and the activation of hepatic stellate cells via TGF-beta 1 and IL-6
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-beta 1 and IL-6 release dose-dependently in hepatocytes. miR-374a could target Myc, a co-transcription factor of both TGF-beta 1 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-beta 1 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 alpha-SMA and Collagen I levels whereas Myc overexpression enhanced FAC-induced activity of HSCs by increasing alpha-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-beta 1 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-beta 1 and IL-6. (C) 2019 Published by Elsevier Inc.