ABSTRACT
Hepatocellular carcinoma (HCC) is a liver tumor that arises in patients with cirrhosis. One of the key players in the progression of cirrhosis to HCC is the hepatic stellate cell, which is activated during liver damage. Activated stellate cells play an essential role in the pathogenesis of HCC by creating a fibrotic micro-environment that sustains tumor growth and by producing 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 hepatic stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which led to a significant reduction in tumor burden and collagen deposition. By co-culturing HCC-cells with hepatic stellate cells, we found that HCC-cells induce ER-stress in hepatic stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which inhibited tumor cell proliferation and migration in different in vitro 2D and 3D co-cultures. Our results suggest that IRE1α is an important mediator in the communication between stellate cells and cancer cells and components of the ER-stress pathway may be therapeutically relevant for slowing down the progression of HCC.
Footnotes
Abbreviations: αSMA - α-smooth muscle actin; DEN - diethylnitrosamine; DMEM - Dulbecco modified eagle medium; ELISA - Enzyme-Linked immune Sorbent Assay, ER - Endoplasmic reticulum; FBS - fetal bovine serum; HCC - Hepatocellular carcinoma, H&E - Haematoxilin-eosin; TBS - tris-buffer saline; TGFβ - tumor growth factor β; UPR - unfolded protein response;
New experiments: western blots, GSEA of human samples, proteomics assay on animal samples