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Retinoic acid receptor-β is downregulated in hepatocellular carcinoma and cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells

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Title: Retinoic acid receptor-β is downregulated in hepatocellular carcinoma and cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells
Authors: Cortes, E
Lachowski, D
Rice, A
Chronopoulos, A
Robinson, B
Thorpe, S
Lee, DA
Possamai, LA
Wang, H
Pinato, DJ
Del Río Hernández, AE
Item Type: Journal Article
Abstract: Hepatic stellate cells (HSCs) are essential perisinusoidal cells in the healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signalling with cancer cells. Since the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-β) in cirrhotic and HCC patients, as well as the effects of RAR-β activation in HSCs. We found that RAR-β expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid (ATRA) promotes HSC deactivation via RAR-β-dependent transcriptional downregulation of myosin light chain 2 (MLC-2) expression. Furthermore, this also abrogated mechanically driven migration towards stiffer substrates. CONCLUSION: Targeting mechanotransduction in HSCs at the transcriptional level may offer new therapeutic options for a range of liver diseases. This article is protected by copyright. All rights reserved.
Issue Date: 1-Feb-2019
Date of Acceptance: 26-Jul-2018
URI: http://hdl.handle.net/10044/1/64632
DOI: https://dx.doi.org/10.1002/hep.30193
ISSN: 0270-9139
Publisher: Wiley
Start Page: 785
End Page: 802
Journal / Book Title: Hepatology
Volume: 69
Issue: 2
Copyright Statement: © 2018 by the American Association for the Study of Liver Diseases. This is the peer reviewed version of the following article, which has been published in final form at https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.30193. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 282051
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
MECHANICAL ACTIVATION
EXTRACELLULAR-MATRIX
LIVER FIBROSIS
CANCER
STIFFNESS
GROWTH
FIBRONECTIN
FIBROBLASTS
MODULATION
PRESTRESS
ATRA
hepatic stellate cells
mechanotransduction
myosin light chain 2
retinoic acid receptor beta
1103 Clinical Sciences
1101 Medical Biochemistry and Metabolomics
Gastroenterology & Hepatology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-07-28
Appears in Collections:Faculty of Engineering
Bioengineering
Division of Surgery
Division of Cancer
Faculty of Medicine



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