System analysis based on the ER stress-related genes identifies WFS1 as a novel therapy target for colon cancer

Background: Colon cancer (COAD) is the third-largest common malignant tumor and the fourth major cause of cancer death in the world. Endoplasmic reticulum (ER) stress has a great influence on cell growth, migration, proliferation, invasion, angiogenesis, and chemoresistance of massive tumors. Although ER stress is known to play an important role in various types of cancer, the prognostic model based on ER stress-related genes (ERSRGs) in colon cancer has not been constructed yet. In this study, we established an ERSRGs prognostic risk model to assess the survival of COAD patients. Methods: The COAD gene expression profile and clinical information data of the training set were obtained from the GEO database (GSE40967) and the test set COAD gene expression profile and clinical informative data were downloaded from the TCGA database. The endoplasmic reticulum stress-related genes (ERSRGs) were obtained from Gene Set Enrichment Analysis (GSEA) website. Differentially expressed ERSRGs between normal samples and COAD samples were identified by R “limma” package. Based on the univariate, lasso, and multivariate Cox regression analysis, we developed an ERSRGs prognostic risk model to predict survival in COAD patients. Finally, we verified the function of WFS1 in COAD through in vitro experiments. Results: We built a 9-gene prognostic risk model based on the univariate, lasso, and multivariate Cox regression analysis. Kaplan-Meier survival analysis and Receiver operating characteristic (ROC) curve revealed that the prognostic risk model has good predictive performance. Subsequently, we screened 60 compounds with significant differences in the estimated half-maximal inhibitory concentration (IC50) between high-risk and low-risk groups. In addition, we found that the ERSRGs prognostic risk model was related to immune cell infiltration and the expression of immune checkpoint molecules. Finally, we determined that knockdown of the expression of WFS1 inhibits the proliferation of colon cancer cells. Conclusions: The prognostic risk model we built may help clinicians accurately predict the survival of patients with COAD. Our findings provide valuable insights into the role of ERSRGs in COAD and may provide new targets for COAD therapy.