Synergistic antifibrotic effects of miR-451 with miR-185 partly by co-targeting EphB2 on hepatic stellate cells

Abstract

Liver fibrosis is a global health problem currently without clinically approved drugs. It is characterized by the excessive accumulation of extracellular matrix (ECM) mainly produced by activated hepatic stellate cells (HSCs). Uncovering the mechanisms underlying the fibrogenic responses in HSCs may have profound translational implications. Erythropoietin-producing hepatocellular receptor B2 (EphB2) is a receptor tyrosine kinase that has been indicated to be a novel profibrotic factor involved in liver fibrogenesis. In the present study, we investigated the effects of miR-451 and miR-185 on the expression of EphB2 and their roles in liver fibrogenesis both in vitro and in vivo. We found that EphB2 upregulation is a direct downstream molecular event of decreased expression of miR-451 and miR-185 in the process of liver fibrosis. Moreover, miR-451 was unexpectedly found to upregulate miR-185 expression at the post-transcriptional level by directly targeting the nuclear export receptor exportin 1 (XPO-1) and synergistically suppress HSCs activation with miR-185. To investigate the clinical potential of these miRNAs, miR-451/miR-185 agomirs were injected individually or jointly into CCl4-treated mice. The results showed that coadministration of these agomirs synergistically alleviated liver fibrosis in vivo. These findings indicate that miR-451 and miR-451/XPO-1/miR-185 axis play important and synergistic regulatory roles in hepatic fibrosis partly through co-targeting EphB2, which provides a novel therapeutic strategy for the treatment of hepatic fibrosis.

The Roles of EphB2 in Cancer

“…In contrast, replacing them with glutamic acid, which like phosphotyrosine is negatively charged, will disrupt SH2 domain binding without impairing EphB2 kinase activity ( Zisch et al, 2000 ). Functionally, Ephb2 is related to monocyte adhesion to endothelial cells ( Vreeken et al, 2020 ), endothelial cell chemotaxis and branching remodeling ( Salvucci et al, 2006 ), T-cell and B-cell activation ( Nguyen et al, 2013 ; Yu et al, 2014 ; Mimche et al, 2015a ), autophagic cell death ( Kandouz et al, 2010 ; Tanabe et al, 2011 ), cell repulsive responses ( Lin et al, 2008 ; Poliakov et al, 2008 ; Schaupp et al, 2014 ; Gaitanos et al, 2016 ; Okumura et al, 2017 ; Evergren et al, 2018 ), platelet function ( Vaiyapuri et al, 2015 ; Berndt and Andrews, 2018 ; Berrou et al, 2018 ), angiogenesis ( Sato et al, 2019 ), and liver fibrosis ( Mimche et al, 2015b ; Butler and Schmidt, 2015 ; Mimche et al, 2018 ; Chen et al, 2020 ; Huang et al, 2021 ).…”

Mixed Nanoscale Liposomes Co-Encapsulating Curcumin and Berberine Inhibit Activated Hepatic Stellate Cell-Induced Drug Resistance and Tumor Metastasis

“…Recent reports showed that cancer cells grew in TME, in which CAFs and other components inhibited drug detention and penetration. , A drug detention assay was carried out on the SMMC-7721 + LX-2 research model using flow cytometry. C6, a fluorescent dye, was chosen to replace CUR for the evaluation of drug uptake.…”

circMELK promotes glioblastoma multiforme cell tumorigenesis through the miR-593/EphB2 axis

“…Luciferase reporter assays confirmed that miR-593 could specifically bind to the 3′ UTR region (site 1) of the EphB2 transcript. Noticeably, miR-451 and miR-185 function as fibrosis suppressors and act synergistically to inhibit liver fibrosis via co-targeting EphB2 , 45 and miR-204 could inhibit the proliferation and invasion of human cervical cancer via targeting EphB2. 46 Hence, it is important in our further studies to find whether there exist some other miRNAs that also bind to site 1 or nearby loci of EphB2 and function synergistically with miR-593 in glioma.…”