The Role of Endoplasmic Reticulum Stress and Hepatic Stellate Cells in Inducing Chemoresistance in Hepatocellular Carcinoma

Abstract: Hepatocellular carcinoma (HCC) is the most common liver malignancy that usually develops in patients suffering from chronic liver diseases. One of the major problems faced in the treatment of HCC is severe chemoresistance. Endoplasmic reticulum (ER) stress and hepatic stellate cells play an important role in tumour survival and growth as well as fibrosis. This study further investigates the crosstalk between ER-stress and hepatic stellate cells in HCC resistant cells as well as their relation to chemoresistance markers expression. Mice with chemically induced HCC were divided in 3 different treatment group; one was only treated with doxorubicin, one only with pharmacological ER-stress inhibitor 4μ8C, and one was treated with a combination of doxorubicin and 4μ8C. Tumour burden, fibrosis and cell proliferation were assessed through histological analysis and ImageJ processing. Chemoresistance markers expression was evaluated through mRNAs determination using real-time qPCR. While the combined treatment consisting of doxorubicin and pharmacological ER-stress inhibitor (4μ8C) has shown to positively reduce tumour progression, ferroptosis and collagen deposition, consequently decreasing fibrosis, drug resistance markers’ expression, on the other hand, seems to be more intricate, thus indicating that further investigations are probably needed.