A risk signature based on endoplasmic reticulum stress-associated genes predicts prognosis and immunity in pancreatic cancer

Abstract

Introduction: The involvement of endoplasmic reticulum (ER) stress in cancer biology is increasingly recognized, yet its role in pancreatic cancer (PC) remains unclear. This study aims to elucidate the impact of ER stress on prognosis and biological characteristics in PC patients.Methods: A bioinformatic analysis was conducted using RNA-seq data and clinicopathological information from PC patients in the TCGA and ICGC databases. The ER stress-associated gene sets were extracted from MSigDB. ER stress-associated genes closely linked with overall survival (OS) of PC patients were identified via log-rank test and univariate Cox analysis, and further narrowed by LASSO method. A risk signature associated with ER stress was formulated using multivariate Cox regression and assessed through Kaplan-Meier curves, receiver operating characteristic (ROC) analyses, and Harrell’s concordance index. External validation was performed with the ICGC cohort. The single-sample gene-set enrichment analysis (ssGSEA) algorithm appraised the immune cell infiltration landscape.Results: Worse OS in PC patients with high-risk signature score was observed. Multivariate analysis underscored our ER stress-associated signature as a valuable and independent predictor of prognosis. Importantly, these results based on TCGA were further validated in ICGC dataset. In addition, our risk signature was closely associated with homeostasis, protein secretion, and immune regulation in PC patients. In particular, PC microenvironment in the high-risk cluster exhibited a more immunosuppressive status. At last, we established a nomogram model by incorporating the risk signature and clinicopathological parameters, which behaves better in predicting prognosis of PC patients.Discussion: This comprehensive molecular analysis presents a new predictive model for the prognosis of PC patients, highlighting ER stress as a potential therapeutic target. Besides, the findings indicate that ER stress can have effect modulating PC immune responses.

Glutathione‑degrading enzymes in the complex landscape of tumors (Review)

“…Simultaneously, changes in the tumor microenvironment generate persistent ER stress signals in various types of tumor ( 95 ) such as colorectal ( 96 ), pancreatic cancer ( 97 ) and so on. This state has a dual effect on tumor cells, on one hand controlling several tumor-promoting features, on the other hand dynamically reprogramming immune cells and inducing tumor cells autophagy, apoptosis and ferroptosis ( 95 ).…”

Identification of endoplasmic reticulum stress-related gene signature reveals KRT8 as a target in ovarian cancer ï¿¿

“…In addition, ER-associated proteins including glucose-regulated protein (GRP78) are increased in EOC patients and can be used to predicted survival (Samanta et al 2020). Chen et al established an ER stress-associated risk signature for pc patients and it can be used to guide clinical decision making in the immunotherapy and predict survival (Chen et al 2023a). However, the predictive role of ERS in OC has not been fully elucidated.…”