The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

SIMPLE SUMMARY: We studied the association between the unfolded protein response (UPR) and carcinogenesis, cancer progression, and survival in hepatocellular carcinoma (HCC). We studied 655 HCC patients from 4 independent cohorts using an UPR score. The UPR was enhanced as normal liver became cancerous and as HCC advanced in stage. The UPR was correlated with cancer cell proliferation that was confirmed by multiple parameters. Significantly, a high UPR score was associated with worse patient survival. Interestingly, though UPR was associated with a high mutational load, it was not associated with immune response, immune cell infiltration, or angiogenesis. To our knowledge, this is the first study to investigate the clinical relevance of the unfolded protein response in HCC. ABSTRACT: Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.