MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway.
The activation of hepatic stellates cells (HSCs) is well believed to play a pivotal role in the development of liver fibrosis. MicroRNA-145 (miR-145) is known to suppress the progression of hepatocellular carcinoma, and is previously reported to be associated with Wnt/β-catenin pathway, but its role in the progression of hepatic fibrosis and activation of HSCs remains unknown and is warranted for investigation. In the present study, we found that the expression of miR-145 is significantly down-regulated in vivo in CCl4-induced mice liver fibrosis as well as in transforming growth factor-β1 (TGF-β1) induced HSC-T6 cell lines and human hepatic stellate cell line LX-2 in vitro. Furthermore, over-expression of miR-145 inhibited TGF-β1-induced the activation and proliferation of HSC-T6 cells in vitro. Mechanistically, we identified that zinc finger E-box-binding homeobox 2 (ZEB2), a key mediator of epithelial-to-mesenchymal transition, acted as a functional downstream target for miR-145. Interestingly, ZEB2 was shown to be involved in the TGF-β1-induced HSCs activation by regulating Wnt/β-catenin signaling pathway. Taken together, our results revealed the critical regulatory role of miR-145 in HSCs activation and implied miR-145 as a potential candidate for therapy of hepatic fibrosis by regulation of Wnt/β-catenin through targeting ZEB2.
School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Disease of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
Dan-Dan
DD
Zhou
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Xiao
X
Wang
School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Disease of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
Yang
Y
Wang
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Xin-Jian
XJ
Xiang
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Zi-Cong
ZC
Liang
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Yi
Y
Zhou
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Ang
A
Xu
Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China.
Cheng-Hao
CH
Bi
School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Disease of Anhui Medical University, Anhui Medical University, Hefei 230032, China. Electronic address: amuleizhang@163.com.
Lei
L
Zhang
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000074165:Zinc Finger E-box Binding Homeobox 2
D018398:Homeodomain Proteins; C541010:MIRN145 microRNA, human; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2
Hepatic fibrosis; MicroRNA-145; Wnt signaling; ZEB2