LncRNA-MEG3 inhibits activation of hepatic stellate cells through SMO protein and miR-212

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.

Our emerging understanding of the roles of long non-coding RNAs in normal liver function, disease, and malignancy

“…MEG3 expression is decreased in fibrotic liver tissue and activated in primary HSCs. Overexpression of this lncRNA through a viral induction system also showed anti-fibrotic activity in murine CCl 4 -induced liver fibrosis [110,111]. In the immortalized human HSC line LX-2, MEG3 transcript levels are reduced in response to TGF-β treatment [111].…”

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

“…MEG3 overexpression and its interaction with smoothened (SMO) participated in the suppression of epithelial to mesenchymal transition (EMT). On the other hand, miR-212 regulated the Hh pathway to mediate the effects of MEG3 on the EMT process [49]. These results suggest that MEG3 may play an important role in liver fibrosis progression and stellate cell activation and may serve as a novel potential diagnostic biomarker and therapeutic target for liver fibrosis.…”

“…Chen et al reported that MEG3 serum levels are low in chronic hepatitis B (CHB) patients and negatively correlate with the degree of liver fibrosis [47]. In addition, MEG3 has other mechanisms of inhibiting HSC activation [49]. MEG3 overexpression and its interaction with smoothened (SMO) participated in the suppression of epithelial to mesenchymal transition (EMT).…”

RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Chronic Hepatitis and Acute-on-chronic Liver Failure Caused By HBV

“…LncRNAs induced by HCV infection may regulate the expression of coding genes required for the replication of the virus or regulation of genes involved in the cellular antiviral response 33 . The expression levels of the lncRNA maternally expressed gene 3 (MEG3) 34 and the lincRNA p21 35 have been found to be reduced during liver fibrosis and, thus, may potentially serve as biomarkers of fibrosis. The lncRNA growth arrest-specific transcript 5 (GAS5) inhibits HCV replication 36 and participates in the activation and proliferation of HSCs 37 .…”