A novel gene signature based on endoplasmic reticulum stress for predicting prognosis in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) remains one of the most common human cancers, the death cases induced by HCC are increasing these years. Endoplasmic reticulum stress (ERS) occurs when misfolded proteins cannot be disposed of properly. It is reported that ERS plays a crucial role in the pathogenesis of human malignant tumors. The aim of this study is to construct a novel gene signature based on ERS for predicting prognosis in HCC.

Methods: The data of HCC patients were downloaded from public databases. The Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed to construct ERS-related gene signature. The cases were divided into high- and low-risk groups based on the ERS-related gene signature in The Cancer Genome Atlas (TCGA) cohort. Subsequently, the differences in messenger ribonucleic acid (mRNA) expression patterns, immune status, tumor mutation burden (TMB) and copy number variants (CNV) were investigated between high- and low-risk groups. Then, a predictive nomogram according to the ERS-related gene signature and clinicopathological variables was established. At last, we explored the biological functions of TMX1 which had the biggest coefficient and we investigated the effect of BRSK2 on apoptosis in HCC.

Results: In our study, a 9-gene ERS-related gene signature was constructed. The results showed that patients in the low-risk group had a better prognosis than the high-risk group patients. The results of receiver operating characteristic (ROC) curves revealed that the area under the curve (AUC) was 0.784 at 1 year, 0.780 at 2 years, 0.793 at 3 years in the training set. While in validation cohort, this index was 0.694 at 1 year, 0.622 at 2 years, 0.613 at 3 years respectively. The analysis of immune status revealed an immunosuppressive microenvironment in the high-risk group. The analysis of TMB and CNV revealed that the high-risk group patients had a higher genomic mutation frequency. In Univariate Cox regression analysis, the hazard ratio of RiskScore was 2.718 [95% confidence interval (CI): 2.173-3.399]. In Multivariate Cox regression analysis, the hazard ratio of RiskScore was 2.422 (95% CI: 1.805-3.25). Then, we established a nomogram according to the RiskScore and Eastern Cooperative Oncology Group performance status. The AUCs of the nomogram were 0.851 at 1 year, 0.860 at 2 years, and 0.866 at 3 years. At last, we found that TMX1 knockdown can inhibit the proliferation and migration of Huh7 and HepG2 cells. In addition, BRSK2 knockdown could promote the apoptosis induced by ERS.

Conclusions: In our study, a novel ERS-related gene signature was constructed to predict the prognosis of HCC patients. In addition, TMX1 and BRSK2 could promote the progression of HCC. This study may provide a new understanding for HCC.