MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression article

Liping Ma, Xiaoxue Yang, Rong Wei, Tinghong Ye, Jian Kang Zhou, Maoyao Wen, Ruoting Men, Ping Li, Biao Dong, Lunxu Liu, Xianghui Fu, Heng Xu, Rami I. Aqeilan, Yu Quan Wei, Li Yang*, Yong Peng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

MicroRNAs (miRNAs) have been demonstrated to modulate cellular processes in the liver. However, the role of miRNAs in liver fibrosis is poorly understood. Because the activation of hepatic stellate cells (HSCs) is a pivotal event in the initiation and progression of hepatic fibrosis, we investigate the differential expression of miRNAs in activated and quiescent rat HSCs by microarray analysis and find that miR-214 (miR-214-3p) is significantly upregulated during HSC activation. Moreover, the robust induction of miR-214 is correlated with liver fibrogenesis in carbon tetrachloride (CCl4)-treated rats and mice, high-fat diet-induced non-alcoholic steatohepatitis in mice, and cirrhosis in humans. We identify that miR-214 expression is driven by the helix-loop-helix transcription factor Twist1 via the E-box element. The increased miR-214 inhibits the expression of suppressor-of-fused homolog (Sufu), a negative regulator of the Hedgehog signaling pathway, thereby contributing to HSC activation to promote the accumulation of fibrous extracellular matrix and the expression of profibrotic genes in HSCs and LX2 cells. Furthermore, miR-214 expression is inversely correlated with the expression of Sufu in clinical cirrhosis samples. To explore the clinical potential of miR-214, we inject antagomiR-214 oligos into mice to induce hepatic fibrosis. The knockdown of miR-214 in vivo enhances Sufu expression and reduces fibrosis marker expression, which ameliorates liver fibrosis in mice. In conclusions, the Twist1-regulated miR-214 promotes the activation of HSC cells through targeting Sufu involved in the Hedgehog pathway and participates in the development of hepatic fibrosis. Hence, the knockdown of miR-214 expression may be a promising therapeutic strategy for liver fibrosis.

Original languageAmerican English
Article number718
JournalCell Death and Disease
Volume9
Issue number7
DOIs
StatePublished - 1 Jul 2018

Bibliographical note

Funding Information:
This study was supported by National Key R&D Program of China (2017YFA0504304 and 2016YFA0502204 to Y.P.) and by National Natural Science Foundation of China (81570554 and 81770568 to L.Y.).

Publisher Copyright:
© 2018 The Author(s).

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