Necroptosis-Related Genes Associated with Immune Activity and Prognosis of Colorectal Cancer

Background: Necroptosis is critical in the occurrence and development of many malignancies, CRC is one of the top causes of cancer-related deaths globally. However, the association between necroptosis-related genes (NRGs) and colorectal cancer (CRC) remains controversial. Therefore, the present study aims to construct a novel signature based on NRG to predict the prognosis of CRC patients and investigate its possible role. Methods: : The transcriptome data from Gene Expression Omnibus (GEO) databases and the Cancer Genome Atlas (TCGA) were utilized to identify cancer hallmarks that are associated with outcomes in colorectal cancer (CRC). A new NRG signature was created and confirmed through least absolute shrinkage and selection operator (LASSO) regression analysis and COX regression analysis. Subsequently, univariate and multivariate Cox regression analysis, K-M survival analysis, ROC, and nomogram were applied to assess the predictive value of our signature. Additionally, the potential mechanisms, tumor immune status, and drug sensitivity differences were uncovered in the two-risk groups by using a variety of bioinformatics analysis algorithms. The expression of signature NRG in CRCs was evaluated through RT-qPCR. Finally, we constructed tumor biological experiments to demonstrated the influence of NRGs on the development of colorectal cancer. Results: : A novel signature consisting of eighteen NRGs (CTSB, PAEP, ARL4C, TAP2, WFS1, BATF2, DUSP27, CXCL9, EPHB2, IRF8, CXCL13, GZMB, APOL6, NLRC5, CXCL10, IRF1, HES6, and PTGDR) was eventually established and verified via stable prediction performance and general applicability for CRC, which was validated in three independent cohorts. Further, stromal and immune cells in the tumor microenvironment (TME) were found to be associated with necroptosis. Additionally, there were significant differences in the sensitivity to anti-tumor agents between the two groups. The qPCR results indicated that these signature NRGs were abnormally expressed in CRC, and the in vitro and in vivo experiments demonstrated that NRGs have a great influence on the progression of CRC. Conclusion: NRG is an accurate predictor of CRC prognosis. Besides，the novel signature displays stable value and translational potential for predicting prognosis, tumor immunogenicity, and therapeutic response in CRC.