Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

Authors

Berit Genz
Miranda A. Coleman
Katharine M. Irvine
Jamie R. Kutasovic
Mariska Miranda
Francis D. Gratte
Janina E. E. Tirnitz-Parker
John K. Olynyk, Edith Cowan UniversityFollow
Diego A. Calvopina
Anna Weis
Nicole Cloonan
Harley Robinson
Michelle M. Hill
Fares Al-Ejeh
Grant A. Ramm

Author Identifier

John Olynyk

https://orcid.org/0000-0003-0417-3411

Document Type

Journal Article

Publication Title

Scientific Reports

ISSN

2045-2322

Volume

9

Issue

1

First Page

8541

Last Page

8541

PubMed ID

31189969

Publisher

Nature Publishing Group

School

School of Medical and Health Sciences

RAS ID

28838

Funders

Funding information available at: https://doi.org/10.1038/s41598-019-44865-1

Grant Number

NHMRC Number : 1048740

Grant Link

http://purl.org/au-research/grants/nhmrc/1048740

Comments

Genz, B., Coleman, M. A., Irvine, K. M., Kutasovic, J. R., Miranda, M., Gratte, F. D., ... Ramm, G. A. (2019). Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells. Scientific Reports, 9(1), Article 8541. Available here

Abstract

During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.

DOI

10.1038/s41598-019-44865-1

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.