A novel high-risk model identified by epithelial-mesenchymal transition predicts prognosis and radioresistance in rectal cancer.

ABSTRACT

Many studies have shown that tumor cells that survive radiotherapy are more likely to metastasize, but the underlying mechanism remains unclear. Here we aimed to identify epithelial-mesenchymal transition (EMT)-related key genes, which associated with prognosis and radiosensitivity in rectal cancer. First, we obtained differentially expressed genes by analyzing the RNA expression profiles of rectal cancer retrieved from The Cancer Genome Atlas database, EMT-related genes, and radiotherapy-related databases, respectively. Then, Lasso and Cox regression analyses were used to establish an EMT-related prognosis model (EMTPM) based on the identified independent protective factor Fibulin5 (FBLN5) and independent risk gene EHMT2. The high-EMTPM group exhibited significantly poorer prognosis. Then, we evaluated the signature in an external clinical validation cohort. Through in vivo experiments, we further demonstrated that EMTPM effectively distinguishes radioresistant from radiosensitive patients with rectal cancer. Moreover, individuals in the high-EMTPM group showed increased expression of immune checkpoints compared to their counterparts. Finally, pan-cancer analysis of the EMTPM model also indicated its potential for predicting the prognosis of lung squamous cell carcinoma and breast cancer patients undergoing radiotherapy. In summary, we established a novel predictive model for rectal cancer prognosis and radioresistance based on FBLN5 and EHMT2 expressions, and suggested that immune microenvironment may be involved in the process of radioresistance. This predictive model could be used to select management strategies for rectal cancer.