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Inhibiting IRE1?-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma.


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 IRE1?-inhibitor 4?8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IRE? in stellate cells, thereby contributing to their activation. Inhibiting IRE1? 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 IRE1? in tumor cells.

SUBMITTER: Pavlovic N 

PROVIDER: S-EPMC7661042 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Pavlović Nataša N   Calitz Carlemi C   Thanapirom Kess K   Mazza Guiseppe G   Rombouts Krista K   Gerwins Pär P   Heindryckx Femke F  

eLife 20201026


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 tum  ...[more]

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