Blocking IRE1a-endoribonuclease Activity in Hepatic Stellate Cells Decreases Tumor Cell Proliferation and Metastasis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a liver tumor that 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 induce ER-stress in 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 HCC-patients.Impact statement 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 liver cancer.* 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;