MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis
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MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs).
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.
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.
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.
KeywordsLiver cirrhosis miRNA TGFβ1 Hepatic stellate cells miR-744
Hepatic stellate cell
Transforming growth factor β
Chronic hepatitis B
Quantitative reverse transcription polymerase chain reaction
Glyceraldehyde 3-phosphate dehydrogenase
Shanghai University of Traditional Chinese Medicine
Phosphate buffered saline
Analysis of variance
This work is supported by National Natural Science Foundation of China (No. 81530101), NIH CA187152 and CA222467.
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.
Compliance with ethical standards
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 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.
Informed consent was collected from patients to approve utilization of their samples for research purposes.
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