A Notch signal pathway related gene signature predicts overall survival in colorectal cancer

Colorectal cancer (CRC) is a prevalent malignancy worldwide, characterized by high morbidity and mortality rates. The notch signaling pathway plays a dual role as both a tumor suppressor and promoter during embryonic development. However, the precise role and underlying mechanisms of notch signal pathway-related genes in CRC remain unclear. In this study, a prognostic signature for CRC was established using CRC datasets from The Cancer Genome Atlas (TCGA) as the training datasets and two Gene Expression Omnibus (GEO) datasets for external validation. The limma R package was first used to screen the differentially expressed genes (DEGs) of the Notch pathway in CRC from TCGA datasets. The univariate Cox regression analysis identified 12 Notch pathway related genes (NPRG) that were significantly associated with overall survival (OS) in CRC. Next, the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to establish a 2-gene prognostic signature (HEYL & WNT5A). Receiver operating characteristic (ROC) curve showed that the 2-gene prognostic signature could effectively predict the 1-, 2-, and 3-year survival time of CRC patients. In addition, the prognostic value of the 2-gene signature was validated in two GEO CORD&READ cohorts. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the signaling pathways and cellular processes associated with the 2-gene signature. A nomogram for predicting the OS of CRC patients was constructed by integrating clinical characteristics and the 2-gene NPRG signature, followed by validation using calibration curves and decision curve analysis (DCA) plots. The NPRG prognostic signature for CRC was established. HEYL and WNT5A were identified as hub genes of the Notch pathway in CRC. HEYL was significantly up-regulated in the high-risk group, while WNT5A was significantly up-regulated in the low-risk group. High expression of HEYL was associated with a poorer prognosis of CRC. Furthermore, Knockout of HEYL significantly inhibited the proliferation of CRC cells in HCT116 and RKO cell lines in vitro experiments. Our research suggests that the 2-gene signature described here can serve as a reliable prognostic biomarker for predicting the prognosis of CRC patients.