MicroRNA-30a Suppresses the Activation of Hepatic Stellate Cells by Inhibiting Epithelial-to-Mesenchymal Transition

Abstract

Background/Aims: The activation of hepatic stellate cells (HSCs) is considered as a pivotal event in liver fibrosis and epithelial-mesenchymal transition (EMT) process has been reported to be involved in HSC activation. It is known that microRNAs (miRNAs) play a pro-fibrotic or anti-fibrotic role in HSC activation. Recently, emerging studies show that miR-30a is down-regulated in human cancers and over-expression of miR-30a inhibits tumor growth and invasion via suppressing EMT process. However, whether miR-30a could regulate EMT process in HSC activation is still unclear. Methods: miR-30a expression was quantified using real-time PCR in carbon tetrachloride (CCl₄)-induced rat liver fibrosis, activated HSCs and patients with cirrhosis. Roles of miR-30a in liver fibrosis in vivo and in vitro were also analyzed. Luciferase activity assays were performed to examine the binding of miR-30a to the 3′-untranslated region of snail family transcriptional repressor 1 (Snai1). Results: miR-30a was down-regulated in human cirrhotic tissues. In CCl₄ rats, reduced miR-30a was found in fibrotic liver tissues as well as isolated HSCs. There was a significant reduction in miR-30a in primary HSCs during culture days. miR-30a over-expression resulted in the suppression of CCl₄-induced liver fibrosis. Restoration of miR-30a led to the inhibition of HSC activation including cell proliferation, α-SMA and collagen expression. Notably, miR-30a inhibited EMT process, with a reduction in TGF-β1 and Vimentin as well as an increase in GFAP and E-cadherin. miR-30a induced a significant reduction in Snai1 protein expression when compared with the control. Interestingly, Snail protein expression was increased during liver fibrosis, indicating that there may be a negative correlation between miR-30a level and Snai1 protein expression. Further studies demonstrated that Snai1 was a target of miR-30a. Conclusion: Our results suggest that miR-30a inhibits EMT process, at least in part, via reduction of Snai1, leading to the suppression of HSC activation in liver fibrosis.

Icariin‐induced miR‐875‐5p attenuates epithelial‐mesenchymal transition by targeting hedgehog signaling in liver fibrosis

“…Overexpression of miR-30a inhibits EMT via downregulation of snail family transcriptional repressor 1 (Snai1), leading to suppress HSCs activation in liver fibrosis. 34 In our current study, we identified that miR-875-5p was markedly decreased in human cirrhotic tissues, fibrotic liver tissues, and primary HSCs from CCL 4 mice, suggesting low levels of miR-875-5p are beneficial for liver fibrosis progression. Interestingly, we demonstrated that icariin could enhance miR-875-5p expression, and knockdown of miR-875-5p impaired the effect of icariin on murine HSCs.…”

“…For example, Zhang et al, reported that miR‐30a was downregulated in human cirrhotic tissues and fibrotic liver tissues from CCL 4 rats. Overexpression of miR‐30a inhibits EMT via downregulation of snail family transcriptional repressor 1 (Snai1), leading to suppress HSCs activation in liver fibrosis . In our current study, we identified that miR‐875‐5p was markedly decreased in human cirrhotic tissues, fibrotic liver tissues, and primary HSCs from CCL 4 mice, suggesting low levels of miR‐875‐5p are beneficial for liver fibrosis progression.…”

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

“…Activation of hepatic stellate cells (HSCs) involves the transition from a quiescent to a proliferative, migratory and fibrogenic phenotype (i.e., myofibroblast) which is characteristic of liver fibrogenesis. To date, multiple cell-surface, cytoplasmic and nuclear molecular signals and pathways have been reported to modulate HSC activation, including cytokines ( Syn et al, 2011 , 2012 ); adipocytokines ( Saxena and Anania, 2015 ; Coombes et al, 2016 ); Toll-like receptors (TLRs) ( Chou et al, 2012 ; Seo et al, 2016 ); Interleukins (ILs) ( Jiao et al, 2016 ); collagen receptors ( Liu et al, 2017 ); nuclear receptors ( Beaven et al, 2011 ; Ding et al, 2013 ; Li et al, 2014 ; Palumbo-Zerr et al, 2015 ; Duran et al, 2016 ); G protein-coupled receptors (GPCRs) ( Li et al, 2015 , 2016a ; Le et al, 2018 ); autophagy ( Thoen et al, 2011 , 2012 ; Hernández-Gea and Friedman, 2012 ; Hernández-Gea et al, 2012 ); endoplasmic reticulum stress ( Hernández-Gea et al, 2013 ; Koo et al, 2016 ); oxidative stress ( Lan et al, 2015 ; Ou et al, 2018 ); epigenetics ( Coll et al, 2015 ; Hyun et al, 2016 ; Kweon et al, 2016 ; Huang et al, 2018 ; Zheng et al, 2018 ); cell metabolism ( Nwosu et al, 2016 ; Du et al, 2018 ; Franko et al, 2018 ; Zhang et al, 2018 ), etc. In addition, extracellular/paracrine signals from resident and inflammatory cells including hepatocytes ( Zhan et al, 2006 ), macrophages ( Pradere et al, 2013 ), natural killer cells ( Glässner et al, 2012 ), natural killer T cells ( Wehr et al, 2013 ), liver sinusoidal endothelial cells (LSECs) ( Xie et al, 2012 ), platelets ( Kurokawa et al, 2016 ), and B cells ( Thapa et al, 2015 ) further promote HSC activation.…”

Loureirin B inhibits the proliferation of hepatic stellate cells and the Wnt/β-catenin signaling pathway by regulating miR-148-3p

“…The activation of HSCs is considered an important event in liver fibrosis, and epithelial–mesenchymal transition (EMT) plays an important role in HSC activation [ 9 ]. HSCs have several important functions under both physiological and pathological conditions associated with sinusoids [ 10 ].…”