Abstract
Activation of hepatic stellate cells (HSCs), a pivotal event in liver fibrosis, is considered as an epithelial–mesenchymal transition (EMT) process. Deregulation of long noncoding RNAs (lncRNAs) has been reported to be involved in a series of human diseases. LncRNA-maternally expressed gene 3 (MEG3) functions as a tumor suppressor in cancers and has been shown to play a vital role in EMT process. However, the biological role of MEG3 in liver fibrosis is largely unknown. In this study, MEG3 was reduced in vivo and in vitro during liver fibrosis. Restoring of MEG3 expression led to the suppression of liver fibrosis, with a reduction in α-SMA and type I collagen. Notably, MEG3 overexpression inhibited HSC activation through EMT, associated with an increase in epithelial markers and a reduction in mesenchymal markers. Further studies showed that Hedgehog (Hh) pathway-mediated EMT process was involved in the effects of MEG3 on HSC activation. Smoothened (SMO) is a member of Hh pathway. Using bioinformatic analysis, an interaction between MEG3 and SMO protein was predicted. This interaction was confirmed by the results of RNA immunoprecipitation and deletion-mapping analysis. Furthermore, MEG3 was confirmed as a target of microRNA-212 (miR-212). miR-212 was partly responsible for the effects of MEG3 on EMT process. Interestingly, MEG3 was also reduced in chronic hepatitis B (CHB) patients with liver fibrosis when compared with healthy controls. MEG3 negatively correlated with fibrosis stage in CHB patients. In conclusion, we demonstrate that MEG3 inhibits Hh-mediated EMT process in liver fibrosis via SMO protein and miR-212.
Highlights
Hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) such as cirrhosis are a major cause of morbidity and mortality worldwide[1]
Upregulation of maternally expressed gene 3 (MEG3) suppressed liver fibrosis via epithelial–mesenchymal transition (EMT) To explore whether EMT process takes a part in the roles of MEG3 in hepatic stellate cells (HSCs) activation, we examined EMT markers including E-cadherin and BMP-7, and Desmin and Vimenin. Quantitative real-time polymerase chain reactionq (qRT-PCR) analysis showed that Adenoviral vectors expressing MEG3 (Ad-MEG3) induced an increase in the mRNA expressions of E-cadherin and BMP-7 and caused a reduction in the mRNA expressions of Desmin and Vimentin in vitro as well as in vivo (Fig. 3a)
It has been demonstrated that restoring of MEG3 expression may contribute to the suppression of tumor cell proliferation and the induction of cell apoptosis[15]
Summary
Hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) such as cirrhosis are a major cause of morbidity and mortality worldwide[1]. A major characteristic of most CLDs, represents the final common pathway of virtually all types of CLDs2. Liver fibrosis, characterized by an excessive accumulation of extracellular matrix (ECM) proteins, is a wound-healing. Epithelial–mesenchymal transition (EMT) is a process where epithelial cells gradually express mesenchymal signatures. EMT process has been demonstrated to be involved in HSC activation[5]. Choi et al found that EMT process in HSC activation is modulated by Hedgehog (Hh) pathway[6]. The main members of Hh family are Sonic
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