Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Xiaoxue Yang, Liping Ma, Rong Wei, Tinghong Ye, Jian Kang Zhou, Maoyao Wen, Ruoting Men, Rami I. Aqeilan, Yong Peng, Li Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.

Original languageAmerican English
Article number75
JournalSignal Transduction and Targeted Therapy
Volume5
Issue number1
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

Funding Information:
This study was supported by National Natural Science Foundation of China (81570554 and 81770568 to L.Y.; 81772960 to YP), National Key R&D Program of China (2016YFA0502204 to Y.P.), Sichuan Science & Technology Program (2019JDTD0013), and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC18030).

Publisher Copyright:
© 2020, The Author(s).

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