<scp>MicroRNA</scp>‐101 suppresses liver fibrosis by targeting the <scp>TGF</scp>β signalling pathway

Tu, Xiaolong; Zhang, Haiyan; Zhang, Jingcheng; Zhao, Shuhua; Zheng, Xiuxiu; Zhang, Zhengping; Zhu, Jie; Chen, Jiangning; Dong, Lei; Zang, Yuhui; Zhang, Junfeng

doi:10.1002/path.4373

Cited by 119 publications

(102 citation statements)

References 52 publications

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“…22,23,35 Additionally, our results indicated that knockdown of MALAT1 alleviates the activation of HSCs and inhibits the progression of liver fibrosis, which may help to open the door to new gene therapies for liver fibrosis. It has been reported that miR-101b is downregulated in liver fibrosis, 7 which was confirmed by our data. Wang et al 27 demonstrated that miR-101 can inhibit MALAT1 expression in esophageal squamous cell carcinoma.…”

Section: Discussionsupporting

confidence: 92%

“…4A), consistent with the previous report. 7 In addition, there was an obviously negative correlation between miR-101b expression and MALAT1 expression in 20 pairs of normal and fibrotic liver tissues (Fig. 4B).…”

Section: Knockdown Of Malat1 Alleviates Mouse Liver Fibrosis In Vivomentioning

confidence: 87%

“…Upregulation of miR-101 inhibits liver fibrosis by targeting the type I TGF-b receptor. 7 Another study indicates that the rs7536540 polymorphism in miR-101-1 is markedly related with development of liver cirrhosis. 8 Additionally, serum miR-101 level can act as a potential biomarker to distinguish HBVassociated liver cirrhosis from HBV-associated hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

Cai

et al. 2015

Cell Cycle

112

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Abbreviations: a-SMA, smooth muscle a-actin; Ad-shCtrl, adenoviral vectors expressing the scrambled shRNA; Ad-shMALAT1, adenoviral vectors expressing shRNA against MALAT1. EdU, 5-Ethyny-2 0 -deoxyuridine; Ago2, Argonaute-2; BDL, bile duct ligation; CCl 4 , carbon tetrachloride; ceRNAs, competing endogenous RNAs; Col1a1, collagen type I, a 1; DMEM, Dulbecco's modified Eagle's medium; HSCs, hepatic stellate cells; IgG, immunoglobulin G; IHC, immunohistochemical; lncRNAs, long noncoding RNAs; MALAT1, Metastasis-associated lung adenocarcinoma transcript 1; miR-101, microRNA-101; miR-NC, miR-101b negative control; miRNAs, microRNAs; ncRNAs, non-coding RNAs; qRT-PCR, quantitative real-time PCR; Rac1, RAS-related C3 botulinum substrate 1; siCtrl, scrambled siRNA; siRNAs, small interfering RNAs.Emerging evidence shows that Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a pivotal role in cell proliferation, migration, and invasion in tumors. However, the biological role and underlying mechanism of MALAT1 in liver fibrosis remains undefined. In this study, up-regulation of MALAT1 was observed in fibrotic liver tissues and in activated hepatic stellate cells (HSCs). In addition, depletion of MALAT1 inhibited the activation of HSCs in vitro and attenuated collagen deposits in vivo. Our results demonstrated that MALAT1 expression is negatively correlated with microRNA-101b (miR-101b) expression. Furthermore, there was a negative feedback loop between the levels of MALAT1 and miR-101b. Luciferase reporter assay indicated that MALAT1 and RAS-related C3 botulinum substrate 1 (Rac1) are targets of miR-101b. We uncovered that MALAT1 regulates Rac1 expression through miR-101b as a competing endogenous RNA (ceRNA), thereby influencing the proliferation, cell cycle and activation of primary HSCs. Collectively, The ceRNA regulatory network may prompt a better understanding of liver fibrogenesis and contribute to a novel therapeutic strategy for liver fibrosis.

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Section: Discussionsupporting

confidence: 92%

Section: Knockdown Of Malat1 Alleviates Mouse Liver Fibrosis In Vivomentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

Cai

et al. 2015

Cell Cycle

112

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“…TGF-β1 has been characterized as the master fibrogenic cytokine stimulating HSC activation and collagen deposition. 21 In our experiments, the rat HSC line, HSC-T6, was treated with different concentrations of TGF-β1, and the effects on miR-17-5p expression examined. TGF-β1 induced an increase in miR-17-5p expression in a dose-dependent manner, ranging from concentrations of 5 to 15 ng/ml (Figure 1a).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

Guo

Chen

et al. 2015

Laboratory Investigation

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A considerable amount of research has focused on the roles of microRNAs (miRNA) in the pathophysiology of liver fibrosis in view of their regulatory effects on hepatic stellate cell (HSC) functions, including proliferation, differentiation, and apoptosis. Recently, miR-17-5p was shown to promote cell proliferation and migration in liver. Transforming growth factor-β1 (TGF-β1) has been characterized as the master fibrogenic cytokine that stimulates HSC activation and promotes progression of liver fibrosis. The issue of whether miR-17-5p plays a role in TGF-β1-induced hepatic fibrogenesis remains to be established. In this study, we demonstrated a dose-/time-dependent increase in miR-17-5p expression in TGF-β1-treated HSCs. Enhanced miR-17-5p expression was additionally observed in CCl 4 -induced rat liver fibrosis. Inhibition of miR-17-5p led to suppression of HSC proliferation induced by TGF-β1 without affecting cellular apoptosis. Notably, miR-17-5p was significantly associated with TGF-β1-induced expression of type I collagen and α-SMA in HSC. Furthermore, Smad7, a negative regulator of the TGF-β/Smad pathway, was confirmed as a direct target of miR-17-5p. Serum miR-17-5p levels were significantly higher in patients with cirrhosis, compared to healthy controls. Our results collectively indicate that miR-17-5p promotes HSC proliferation and activation, at least in part, via reduction of Smad7, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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“…2 Alternatively, microRNAs may be found within gene sequences where they are generally transcribed together with their host genes. 2,3 MicroRNAs participate in a vast range of developmental and physiological processes, including fibrosis, 4,5 cell proliferation, 6 apoptosis, 7 differentiation, 8 metabolism, 9 and angiogenesis. 10 Because of their extensive involvement in cellular processes, derangement of microRNA is associated with disease formation such as in tumorigenesis, 11,12 inflammatory diseases 13,14 and defective neuronal development.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-215 Regulates Fibroblast Function: Insights from a Human Fibrotic Disease

Lan

Chen

Tong³

2015

Cell Cycle

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MicroRNAs are implicated in the regulation of gene expression via various mechanisms in health and disease, including fibrotic processes. Pterygium is an ocular surface condition characterized by abnormal fibroblast proliferation and matrix deposition. We aimed to investigate the role of microRNAs in pterygium and understand the relevant cellular and molecular mechanisms. To achieve this objective, a combination of approaches using surgically excised paired human pterygium and conjunctival tissues as well as cultured primary fibroblast cells from tissue explants were evaluated. Fibroblast dysfunction has been shown to play a central role in pterygium pathology. Here we show that miR-215, among a few others, was down-regulated (2-fold) in pterygium compared to control, and this was consistent in microarray, real-time PCR and fluorescent in-situ hybridization. The effects of increased miR-215 were investigated by adding exogenous miR-215 to fibroblasts, and this showed a decrease in cell proliferation but no significant apoptosis compared to control. Further cell cycle analysis showed that miR-215 depressed progression of cells at G1/S as well as G2/M. A few cell cycle related transcripts were downregulated (2.2-4.5-fold) on addition of miR-215: Mcm3, Dicer1, Cdc25A, Ick, Trip13 and Mcm10. Theoretic binding energies were used to predict miR-215 binding targets and luciferase reporter studies confirmed Mcm10 and Cdc25A as direct targets. In summary, mir-215 could play a role in inhibiting fibroblast proliferation in ocular surface conjunctiva. Dampening of this mir-215 could result in increased fibroblast cell cycling and proliferation, with possibly increased fibroblastic production of matrix, inducing pterygium formation.

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MicroRNA‐101 suppresses liver fibrosis by targeting the TGFβ signalling pathway

Cited by 119 publications

References 52 publications

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

MicroRNA-215 Regulates Fibroblast Function: Insights from a Human Fibrotic Disease

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