Overexpression of miR-126 Inhibits the Activation and Migration of HSCs through Targeting CRK

Gong, Xu-Hua; Chen, Chao; Hou, Peng; Zhu, Shifeng; Wu, Chaoqun; Song, Chenlin; Ni, Wei; Hu, Jiangfeng; Yao, Dengfu; Kang, Jiuhong; Zhu, Liang

doi:10.1159/000356653

Cited by 19 publications

(10 citation statements)

References 18 publications

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“…Cell migration is largely associated with changes in the actin cytoskeleton and enhanced cell proliferation. However, our results show that although the 14‐3‐3ζ‐β‐catenin extracellular vesicles induce large changes in the actin cytoskeleton, namely the re‐assembly of actin stress fibers in thick bundles at the periphery of the cell and the formation of long, condensed stress fibers and changes in cell shape the rates of cell proliferation do not change as has been show in other systems (Gong et al., 2014) (Ponugoti et al., 2013) (Chitanuwat et al., 2013). The main conclusion drown from our data is that extracellular vesicles containing 14‐3‐3ζ and β‐catenin (but not the Wnt3a ligand) activate Wnt signaling in the receiving cells.…”

Section: Discussionsupporting

confidence: 56%

14‐3‐3 and β‐catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway

et al. 2014

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Aberrant activation of the canonical Wnt signal transduction pathway is involved in a large number of human diseases. β-catenin, the key effector protein of the canonical Wnt pathway, functions in the nucleus with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate expression of Wnt target genes. Here we show that members of the 14-3-3 protein family bind disheveled-2 (Dvl-2) and glycogen synthase-3β (GSK-3β) to attenuate the interaction between GSK-3β and β-catenin. Importantly, 14-3-3 and β-catenin form "bleb-like" structures and are secreted via extracellular vesicles to induce Wnt signaling activity in target cells. Our data suggest a novel way of transducing the oncogenic Wnt signal in which β-catenin is regulated by 14-3-3ζ through the formation of "oncosomes" that contain both the 14-3-3 and β-catenin proteins.

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Section: Discussionsupporting

confidence: 56%

14‐3‐3 and β‐catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway

et al. 2014

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“…miRNAs are implicated in a wide variety of biological processes including cell proliferation, apoptosis, metabolism, differentiation, immune response and development [6][7][8]. Over the past several years, gene array analysis of miRNA expression in carbon tetrachloride (CCl 4 )-induced hepatic fibrogenesis model has identified a panel of deregulated miRNAs [9].…”

Section: Introductionmentioning

confidence: 99%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR-378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a-3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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“…Overexpression of miR-126 after transduction with lentiviral vector encoding miR-126 decreased α-SMA and collagen α(1) expression. Although miR-126 decreases HSC migration, it did not affect their proliferation (107).…”

Section: Mir-126mentioning

confidence: 96%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

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Overexpression of miR-126 Inhibits the Activation and Migration of HSCs through Targeting CRK

Cited by 19 publications

References 18 publications

14‐3‐3 and β‐catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway

14‐3‐3 and β‐catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

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