MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7.
A considerable amount of research has focused on the roles of microRNAs (miRNA) in the pathophysiology of liver fibrosis in view of their regulatory effects on hepatic stellate cell (HSC) functions, including proliferation, differentiation, and apoptosis. Recently, miR-17-5p was shown to promote cell proliferation and migration in liver. Transforming growth factor-β1 (TGF-β1) has been characterized as the master fibrogenic cytokine that stimulates HSC activation and promotes progression of liver fibrosis. The issue of whether miR-17-5p plays a role in TGF-β1-induced hepatic fibrogenesis remains to be established. In this study, we demonstrated a dose-/time-dependent increase in miR-17-5p expression in TGF-β1-treated HSCs. Enhanced miR-17-5p expression was additionally observed in CCl4-induced rat liver fibrosis. Inhibition of miR-17-5p led to suppression of HSC proliferation induced by TGF-β1 without affecting cellular apoptosis. Notably, miR-17-5p was significantly associated with TGF-β1-induced expression of type I collagen and α-SMA in HSC. Furthermore, Smad7, a negative regulator of the TGF-β/Smad pathway, was confirmed as a direct target of miR-17-5p. Serum miR-17-5p levels were significantly higher in patients with cirrhosis, compared to healthy controls. Our results collectively indicate that miR-17-5p promotes HSC proliferation and activation, at least in part, via reduction of Smad7, 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, Zhejiang, China.
Fujun
F
Yu
Institute of Organ Transplantation; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Yong
Y
Guo
Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Bicheng
B
Chen
Department of Infectious Diseases; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Peihong
P
Dong
Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Jianjian
J
Zheng
D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D003094:Collagen / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C524941:MIRN17 microRNA, human; C000601368:MIRN17 microRNA, rat; D035683:MicroRNAs; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D003094:Collagen