An EMT-related genes signature as a prognostic biomarker for patients with endometrial cancer

Abstract

BACKGROUND: The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC. METHODS: RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression. RESULTS: A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433-2.798; P < 0.001). The nomogram integrating the risk signature and clinical characteristics exhibited robust validity and performance at predicting EC overall survival indicated by ROC and calibration curve. Functional enrichment analysis revealed that the EMT-related genes risk signature was associated with extracellular matrix organization, mesenchymal development and cellular component morphogenesis, suggesting its possible relevance to epithelial-mesenchymal transition and cancer progression. Functionally, we demonstrated that the silencing of SIX1, SIRT2 and CDKN2A expression could accelerate the migratory and invasive capacities of tumor cells, whereas the downregulation of PGR dramatically inhibited cancer cells migration and invasion. CONCLUSIONS: Altogether, a novel four-EMT-related genes signature was a potential biomarker for EC prognosis. These findings might help to ameliorate the individualized prognostication and therapeutic treatment of EC patients.