A novel epithelial-mesenchymal transition (EMT)-related gene signature of predictive value for the survival outcomes in lung adenocarcinoma.

Abstract

Lung adenocarcinoma (LUAD) is a remarkably heterogeneous and aggressive disease with dismal prognosis of patients. The identification of promising prognostic biomarkers might enable effective diagnosis and treatment of LUAD. Aberrant activation of epithelial-mesenchymal transition (EMT) is required for LUAD initiation, progression and metastasis. With the purpose of identifying a robust EMT-related gene signature (E-signature) to monitor the survival outcomes of LUAD patients. In The Cancer Genome Atlas (TCGA) database, least absolute shrinkage and selection operator (LASSO) analysis and cox regression analysis were conducted to acquire prognostic and EMT-related genes. A 4 EMT-related and prognostic gene signature, comprising dickkopf-like protein 1 (DKK1), lysyl oxidase-like 2 (LOXL2), matrix Gla protein (MGP) and slit guidance ligand 3 (SLIT3), was identified. By the usage of datum derived from TCGA database and Western blotting analysis, compared with adjacent tissue samples, DKK1 and LOXL2 protein expression in LUAD tissue samples were significantly higher, whereas the trend of MGP and SLIT3 expression were opposite. Concurrent with upregulation of epithelial markers and downregulation of mesenchymal markers, knockdown of DKK1 and LOXL2 impeded the migration and invasion of LUAD cells. Simultaneously, MGP and SLIT3 silencing promoted metastasis and induce EMT of LUAD cells. In the TCGA-LUAD set, receiver operating characteristic (ROC) analysis indicated that our risk model based on the identified E-signature was superior to those reported in literatures. Additionally, the E-signature carried robust prognostic significance. The validity of prediction in the E-signature was validated by the three independent datasets obtained from Gene Expression Omnibus (GEO) database. The probabilistic nomogram including the E-signature, pathological T stage and N stage was constructed and the nomogram demonstrated satisfactory discrimination and calibration. In LUAD patients, the E-signature risk score was associated with T stage, N stage, M stage and TNM stage. GSEA (gene set enrichment analysis) analysis indicated that the E-signature might be linked to the pathways including GLYCOLYSIS, MYC TARGETS, DNA REPAIR and so on. In conclusion, our study explored an innovative EMT based prognostic signature that might serve as a potential target for personalized and precision medicine.