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MicroRNA-489-3p Represses Hepatic Stellate Cells Activation by Negatively Regulating the JAG1/Notch3 Signaling Pathway

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Abstract

Background

The transformation of hepatic stellate cells (HSCs) into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis. Recent studies have shown that microRNAs (miRNAs) play a critical role in the transformation of HSCs. However, the function of miR-489-3p in liver fibrosis remains unclear.

Methods

Here, we detected the levels of miR-489-3p and jagged canonical Notch ligand 1 (JAG1) in liver fibrosis by using CCl4-treated rats as an in vivo model and transforming growth factor-beta 1 (TGF-β1)-treated HSC cell lines LX-2 and HSC-T6 as in vitro models. The expression of profibrotic markers was affected by transfecting LX-2 cells with either miR-489-3p mimic or si-JAG1. A dual-luciferase reporter assay was carried out to study the interaction of JAG1 with miR-489-3p.

Results

We found that miR-489-3p was remarkably decreased while JAG1 was increased in liver fibrosis models both in vivo and in vitro. Overexpression of miR-489-3p reduced the expression of profibrotic markers and the activation of LX-2 cells induced by TGF-β1. Moreover, miR-489-3p decreased the expression of jagged canonical Notch ligand 1 (JAG1) in LX-2 cells by interacting with its 3ʹ-UTR. As JAG1 is a Notch ligand, decreased JAG1 by miR-489-3p inhibited the Notch signaling pathway. Moreover, the downregulation of JAG1 inhibited the expression of fibrotic markers.

Conclusion

Our results indicate that miR-489-3p can inhibit HSC activation by inhibiting the JAG1/Notch3 signaling pathway.

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Funding

This work was supported by the Innovation Cultivation Program of Zhongnan Hospital of Wuhan University [znpy2018095] and the National Natural Science Foundation of China [81670554].

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Authors and Affiliations

  1. Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China

    Juanjuan Li, Shouquan Dong, Mingliang Ye, Ganjing Peng, Jie Luo, Chun Wang, Jing Wang, Qiu Zhao, Ying Chang & Hongling Wang

  2. The Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, Hubei, China

    Hongling Wang

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  1. Juanjuan Li
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Correspondence to Hongling Wang.

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The Committee on the Ethics of Animal Experiments of the Wuhan University School of Medicine approved the animal experimental procedures (permit number: 2017055).

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Li, J., Dong, S., Ye, M. et al. MicroRNA-489-3p Represses Hepatic Stellate Cells Activation by Negatively Regulating the JAG1/Notch3 Signaling Pathway. Dig Dis Sci 66, 143–150 (2021). https://doi.org/10.1007/s10620-020-06174-w

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