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MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis

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Abstract

Background

MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs).

Methods

Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched.

Results

The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LC patients’ sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation.

Conclusions

MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir’s action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.

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Abbreviations

LC:

Liver cirrhosis

HSC:

Hepatic stellate cell

ECM:

Extracellular matrix

miRNA:

MicroRNA

UTR:

Untranslated region

TGFβ:

Transforming growth factor β

EMT:

Epithelial-to-mesenchymal transition

CHB:

Chronic hepatitis B

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

SUTCM:

Shanghai University of Traditional Chinese Medicine

CCl4 :

Carbon tetrachloride

PBS:

Phosphate buffered saline

ANOVA:

Analysis of variance

ROC:

Receiver–operator characteristic

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Acknowledgements

This work is supported by National Natural Science Foundation of China (No. 81530101), NIH CA187152 and CA222467.

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Author notes

  1. Shuang Ren and Jiamei Chen contribute equally to this work.

Authors and Affiliations

  1. Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Shuang Ren, Jiamei Chen, Qinglan Wang, Xuewei Li, Ying Xu, Xiao Zhang, Yongping Mu, Hua Zhang & Ping Liu

  2. Traditional Chinese Medicine Department, First Affiliated Hospital of China Medical University, Shenyang, 201203, Liaoning, China

    Shuang Ren

  3. Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32611, USA

    Shuang Huang

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  1. Shuang Ren
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Contributions

SR, SH and PL designed research. SR, JC, XL, WF and XZ performed the experiments and analyzed the data. YM, HZ, MS and CL contributed experimental materials or provided helpful suggestions. SR, JC, SH and PL wrote the manuscript.

Corresponding authors

Correspondence to Shuang Huang or Ping Liu.

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Conflict of interest

Shuang Ren, Jiamei Chen, Qinglan Wang, Xuewei Li, Ying Xu, Xiao Zhang, Yongping Mu, Hua Zhang, Shuang Huang, Ping Liu have no confict of interest to declare.

Ethics approval

Ethics approval all procedures performed in studies involving human participants and animals were in accordance with the ethical standards of Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine. The entire study was approved by Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine.

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Informed consent was collected from patients to approve utilization of their samples for research purposes.

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Ren, S., Chen, J., Wang, Q. et al. MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis. Hepatol Int 13, 814–825 (2019). https://doi.org/10.1007/s12072-019-09993-w

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  • DOI: https://doi.org/10.1007/s12072-019-09993-w

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