Induction of microRNA-214-5p in human and rodent liver fibrosis

Iizuka, Masaaki; Ogawa, Tomohiro; Enomoto, Masaru; Motoyama, Hideki; Yoshizato, Katsutoshi; Ikeda, Kazuo; Kawada, Norifumi

doi:10.1186/1755-1536-5-12

Cited by 75 publications

(65 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…48,49 However, variable expression during liver fibrosis has been reported for miR-214, the other miR encoded by DNM3os, which independently targets the 3 0 -UTR of CCN2 and inhibits expression of CCN2 and other fibrosis-or inflammation-related molecules in HSCs. 10,23,50 Although further experiments are needed to fully clarify the sites of expression and action of the miR-199a-2/214 cluster during progression of chronic liver disease, a principal mechanism regulating its expression in many biological systems involves the basic helix-loop-helix transcription factor, Twist1. 45,51e54 We recently reported that, through its binding of the E-box response element in the upstream region, Twist1 suppresses CCN2 expression in quiescent HSCs by driving, at least in part, miR-214 promoter activity and expression.…”

Section: Discussionmentioning

confidence: 99%

Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p

Chen

Velazquez

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse hepatic stellate cells (HSCs) and directly suppressed production of CCN2. Up-regulated CCN2 expression in fibrotic mouse livers or in activated primary mouse HSCs was associated with miR-199a-5p downregulation. MiR-199a-5p in quiescent mouse HSCs inhibited the activity of a wild-type CCN2 3 0 untranslated region (3 0 -UTR) but not of a mutant CCN2 3 0 -UTR lacking the miR-199a-5p-binding site. In activated mouse HSCs, CCN2, a-smooth muscle actin, and collagen 1(a1) were suppressed by a miR199a-5p mimic, whereas in quiescent mouse HSCs, the inhibited CCN2 3 0 -UTR activity was blocked by a miR-199a-5p antagomir. CCN2 3 0 -UTR activity in human HSCs was reduced by a miR-199a-5p mimic. MiR-199a-5p was present at higher levels in exosomes from quiescent versus activated HSCs. MiR-199a-5pecontaining exosomes were shuttled from quiescent mouse HSCs to activated mouse HSCs in which CCN2 3 0 -UTR activity was then suppressed. Exosomes from quiescent HSCs caused miR-199a-5pe dependent inhibition of CCN2, a-smooth muscle actin, or collagen 1(a1) in activated HSCs in vitro and bound to activated HSCs in vivo. Thus, CCN2 suppression by miR-199a-5p accounts, in part, for lowlevel fibrogenic gene expression in quiescent HSCs and causes dampened gene expression in activated HSCs after horizontal transfer of miR-199a-5p in exosomes from quiescent HSCs. (Am J Pathol 2016, 186: 2921e2933; http://dx

show abstract

Section: Discussionmentioning

confidence: 99%

Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p

Chen

Velazquez

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Forced expression of miR-221/222 promotes the activation of HSCs and the progression of liver fibrosis [10]. Over-expression of miR-214 in HSCs increased the expression of fibrosis-related genes, matrix metalloproteinase (MMP)-2, MMP-9 and α-SMA [11]. The miRNAs miR-150 and miR-194 may suppress the fibrotic phenotype and inhibit the production of ECM [12].…”

Section: Introductionmentioning

confidence: 98%

The role of the miR-31/FIH1 pathway in TGF-β-induced liver fibrosis

Chen

Liu

et al. 2015

Clinical Science

View full text Add to dashboard Cite

The miRNAs are small, non-coding RNAs that regulate various biological processes, including liver fibrosis. Hepatic stellate cells (HSCs) play a central role in the pathogenesis of liver fibrosis. By microarray profiling and real-time PCR, we noted that miR-31 expression in HSCs from rats, mice and humans was significantly increased during HSC activation in culture. Overall, miR-31 expression levels were unchanged in the whole-liver RNA extracts from fibrotic rat and human samples. Nevertheless, we found that miR-31 was particularly up-regulated in HSCs but not in hepatocytes during fibrogenesis. Thus, we hypothesized that miR-31 may mediate liver fibrosis. In the present study, we found that inhibition of miR-31 expression significantly inhibited HSC activation, whereas its over-expression obviously promoted HSC activation. Moreover, over-expression of miR-31 promoted HSC migration by enhancing matrix metalloproteinase (MMP)-2 expression whereas inhibition of miR-31 has an opposite effect. The biological function of miR-31 during HSC activation might be through targeting FIH1, a suppressor of hypoxia-inducible factor (HIF-1), because a knockdown of FIH1 by shRNA could mimic the effects of miR-31. In addition, primary rat HSCs were isolated and treated with different cytokines, such as transforming growth factor β (TGF-β), vascular endothelial growth factor and platelet-derived growth factor-BB, to evaluate upstream regulators of miR-31. We found that only TGF-β, a pivotal regulator in liver fibrosis, remarkably increased miR-31 expression in HSCs. And the effects of TGF-β on HSCs can be partially counteracted by inhibition of miR-31. In addition, chromatin immunoprecipitation experiments and the luciferase reporter assay demonstrated that Smad3, a major TGF-β-downstream transcription factor, stimulated the transcription activity of miR-31 by binding directly to miR-31's promoter. In conclusion, the miR-31/FIH1 pathway associates with liver fibrosis, perhaps by participation in the TGF-β/Smad3 signalling of HSCs.

show abstract

“…16 Upregulation of Twist-positive cells is associated with liver and kidney fibrosis. 17,18 The role of twist in areca nut chewing-associated OSF also remains unknown. However, it is unclear whether Twist is involved in the pathogenesis of OSF.…”

Section: Introductionmentioning

confidence: 99%