MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4.
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.
School of pharmacy, Anhui key laboratory of bioactivity of natrual products, Anhui Medical University, Hefei, China.
Yong
Y
He
Cheng
C
Huang
Xu
X
Sun
Xiao-ran
XR
Long
Xiong-wen
XW
Lv
Jun
J
Li
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051901:Smad4 Protein / Q000235:genetics* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
D000199:Actins; D035683:MicroRNAs; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; C554180:MIRN146 microRNA, rat; C490811:Smad4 protein, rat; C498862:Acta2 protein, rat