Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Abstract
Data availability
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Abstract

Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line specific direct effects of inhibiting IRE1α in tumor cells.

Data availability

Proteomics data has been deposited in Dryad with the following DOI: https://doi.org/10.5061/dryad.6wwpzgmv2

The following data sets were generated

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Dryad Digital Repository, doi:10.5061/dryad.6wwpzgmv2.

http://dx.doi.org/10.5061/dryad.6wwpzgmv2

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Article and author information

Author details

Nataša Pavlović

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

Competing interests
The authors declare that no competing interests exist.
Carlemi Calitz

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

Competing interests
The authors declare that no competing interests exist.
Kess Thanapirom

University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Guiseppe Mazza

University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Krista Rombouts

University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Pär Gerwins

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

Competing interests
The authors declare that no competing interests exist.
Femke Heindryckx

Medical Cell Biology, Uppsala University, Uppsala, Sweden

For correspondence
femke.heindryckx@mcb.uu.se

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1987-7676

Funding

Cancerfonden (CAN 2017/518)

Femke Heindryckx

Svenska Sällskapet för Medicinsk Forskning (S17-0092)

Femke Heindryckx

OE och Edla Johanssons stiftelse

Femke Heindryckx

Olga Jonssons stiftelse

Femke Heindryckx

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations by FELASA. All of the animals were handled according to approved institutional animal care and Uppsala University approved protocols were used. The protocol was approved by the Committee on the Ethics of Animal Experiments of Uppsala (C95/14). All effort was made to minimise suffering and to decrease animal usage.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.