Participation of miR-200a in TGF-β1-mediated hepatic stellate cell activation.
Hepatic stellate cell (HSC) activation is a pivotal event in the initiation and progression of hepatic fibrosis since it mediates transforming growth factor beta 1 (TGF-β1)-driven extracellular matrix (ECM) deposition. MicroRNAs (miRNAs), small non-coding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key factors to regulate cell proliferation, differentiation, and apoptosis. Although the function of miR-200a has been discussed in many cancers and fibrotic diseases, its role in hepatic fibrosis is still poorly understood. The aim of this study is to investigate whether miR-200a could attenuate hepatic fibrosis partly through Wnt/β-catenin and TGF-β-dependant mechanisms. Our study found that the expression of endogenous miR-200a was decreased in vitro in TGF-β1-induced HSC activation as well as in vivo in CCl4-induced rat liver fibrosis. Overexpression of miR-200a significantly inhibited α-SMA activity and further affected the proliferation of TGF-β1-dependent activation of HSC. In addition, we identified β-catenin and TGF-β2 as two functional downstream targets for miR-200a. Interestingly, miR-200a specifically suppressed β-catenin in the protein level, whereas miR-200a-mediated suppression of TGF-β2 was shown on both mRNA and protein levels. Our results revealed the critical regulatory role of miR-200a in HSC activation and implied miR-200a as a potential candidate for therapy by deregulation of Wnt/β-catenin and TGFβ signaling pathways, at least in part, via decreasing the expression of β-catenin and TGF-β2.
School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Mei Shan Road, Hefei, 230032, Anhui Province, People's Republic of China.
Xu
X
Sun
Yong
Y
He
Tao-Tao
TT
Ma
Cheng
C
Huang
Lei
L
Zhang
Jun
J
Li
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002251:Carbon Tetrachloride; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix; D057809:HEK293 Cells; D055166:Hepatic Stellate Cells / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
D000199:Actins; D002251:Carbon Tetrachloride; D035683:MicroRNAs; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D051176:beta Catenin; C555600:MIRN200 microRNA, rat; C498862:Acta2 protein, rat