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Updated: May 21, 2026
Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4
1School of pharmacy, Anhui key laboratory of bioactivity of natrual products, Anhui Medical University, Hefei, China.
Abstract:
Activation of hepatic stellate cells (HSC) plays a pivotal role in the development of hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor responsible for the activation of HSC. MicroRNAs (miRNAs) have recently been shown to regulate cell proliferation, differentiation, and apoptosis. The involvement of miRNAs and their roles in TGF-β1-induced HSC activation remains largely unknown. Our study found that the expression of miR-146a was downregulated in HSC in response to TGF-β1 stimulation in dose-dependent manner by one-step real-time quantitative PCR. Moreover, we sought to examine whether miR-146a became dysregulated in CCl(4)-induced hepatic fibrosis in rats. Our study revealed that miR-146a was downregulated in liver fibrotic tissues. In addition, The HSC transfected with miR-146a mimics exhibited attendated TGF-β1-induced α-smooth muscle actin (α-SMA) expression compared with the control. Furthermore, overexpression of miR-146a suppressed TGF-β-induced HSC proliferation, and increased HSC apoptosis. Bioinformatics analyses predict that SMAD4 is the potential target of miR-146a. MiR-146a overexpression in TGF-β1-treated HSC did not decrease target mRNA levels, but significantly reduced target protein expression. These results suggested that miR-146a may function as a novel regulator to modulate HSC activation during TGF-β1 induction by targeting SMAD4.
Insights
MicroRNAs (miRNAs), specifically miR-146a, are downregulated during liver fibrosis. Restoring miR-146a levels inhibits hepatic stellate cell activation by targeting SMAD4, offering a potential therapeutic strategy.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Hepatic stellate cell (HSC) activation is central to liver fibrosis development.
- Transforming growth factor-β1 (TGF-β1) is a primary driver of HSC activation.
- The role of microRNAs (miRNAs) in TGF-β1-induced HSC activation is largely unexplored.
Purpose of the Study:
- To investigate the role of miR-146a in TGF-β1-induced HSC activation.
- To determine if miR-146a is dysregulated in carbon tetrachloride (CCl4)-induced liver fibrosis.
- To explore the potential of miR-146a as a therapeutic target for liver fibrosis.
Main Methods:
- Quantitative real-time PCR to measure miR-146a expression.
- In vitro studies involving TGF-β1 stimulation of HSC and miR-146a mimic transfection.
- In vivo studies using a CCl4-induced rat model of liver fibrosis.
- Bioinformatics analysis to predict miR-146a targets.
Main Results:
- miR-146a expression was downregulated in HSC upon TGF-β1 stimulation in a dose-dependent manner.
- miR-146a was also found to be downregulated in fibrotic liver tissues from rats.
- Overexpression of miR-146a attenuated TGF-β1-induced α-smooth muscle actin (α-SMA) expression, suppressed HSC proliferation, and increased apoptosis.
- Bioinformatics predicted SMAD4 as a target, and miR-146a overexpression reduced SMAD4 protein levels without affecting mRNA levels.
Conclusions:
- miR-146a acts as a negative regulator of TGF-β1-induced HSC activation.
- miR-146a targets SMAD4 at the protein level, modulating HSC behavior.
- miR-146a represents a potential therapeutic target for managing liver fibrosis.
