Hypoxia-related Genes as Prognostic Signature to Predict Prognosis and Immune Microenvironment of Colorectal Cancer Patients
Abstract Background: Hypoxia is widespread in solid tumors and is directly associated with colorectal cancer (CRC) aggressiveness, poor prognosis, and immunotherapy resistance. In this study, we aimed at developing a hypoxia-related marker to improve the prognosis prediction in CRC.Methods: We used gene expression data of CRC samples from the Cancer Genome Atlas Database and the hypoxia gene set to obtain a hypoxia gene expression matrice of 479 CRC patients. The prognostic model was constructed by screening hypoxia risk genes that were significantly associated with prognosis by univariate and multivariate Cox regression analysis. The predictive performance of the prognostic model was evaluated by Kaplan-Meier survival curve analyses and ROC curve analysis and validated in the GSE17536 dataset of Gene Expression Omnibus database. Finally, we analyzed the immune cell infiltration and expression of immunosuppressive genes in CRC patients at high and low risk of hypoxia.Results: We constructed a hypoxia risk prognostic model composed of two hypoxia-related genes (SLC2A3 and ENO3), which was proved to have better sensitivity and specificity after a series of validation. Independent prognostic analysis revealed that the risk score can serve as an independent prognostic factor for CRC. The infiltration of natural killer resting cells, activated master cells and T-cell regulatory cells were significantly increased in the hypoxia high-risk group, and Gene Set Enrichment Analysis showed that gene sets involved in tumor proliferation and differentiation, immune tolerance as well as hypoxia were also significantly enriched in this group. Negatively regulated genes in the Cancer Immunity Cycle, as well as immune checkpoints, were upregulated in the high hypoxia risk group, forming an immunosuppressive microenvironment, and mediating the immune escape. Conclusions: In summary, we constructed and validated a reliable hypoxia risk model that can independently predict the prognosis of CRC patients and reflect the status of the immune microenvironment, which is beneficial for screening CRC prognostic biomarkers and therapeutic targets.