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


CONCLUSIONS
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.
Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Fujun
F
Yu
XuFei
X
Fan
Bicheng
B
Chen
Peihong
P
Dong
Jianjian
J
Zheng
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002251:Carbon Tetrachloride; D002453:Cell Cycle; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D017207:Rats, Sprague-Dawley; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D020413:3' Untranslated Regions; C526012:MIRN378 microRNA, human; C572773:MIRN378 microRNA, rat; D035683:MicroRNAs; C484142:WNT10A protein, human; D051153:Wnt Proteins; C500911:Wnt10a protein, rat; D051176:beta Catenin; D002251:Carbon Tetrachloride