Exploring the Role of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma through mining of the Human Protein Atlas

SIMPLE SUMMARY: Hepatocellular carcinoma is a highly deadly primary liver cancer. It is usually diagnosed at a late stage, when therapeutic options are scarce, and the lack of predictive biomarkers poses a challenge for early detection. A known hallmark of hepatocellular carcinoma is the accumulation of misfolded proteins in the endoplasmic reticulum (ER), known as ER-stress. Growing experimental evidence suggests that ER-stress is involved in liver cancer initiation and progression. However, it remains unclear if ER-stress markers can be used as therapeutic targets or biomarkers for patients with liver cancer. In this study, we evaluated the prognostic value of proteins involved in managing ER-stress in liver cancer by mining a publicly available patient-derived database, the Human Protein Atlas. We thereby identified 44 ER-stress-associated proteins as prognostic markers in liver cancer. Furthermore, we discussed the expression of these markers in relation to disease stage, age, sex, ethnicity, and tissue localization. ABSTRACT: Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR’s involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.