Keratin gene signature expression drives epithelial-mesenchymal transition through enhanced TGF-β signaling pathway activation and correlates with adverse prognosis in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD.

Methods: Transcriptome profiles and associated clinical details of LUAD patients were meticulously gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The KGS score was developed based on the expression of five prognostic KRT genes (, , , and ), and the upper quartile of the KGS score was chosen as the cutoff. The Kaplan-Meier method was evaluated to compare survival outcomes between KGS-high and KGS-low groups. The underlying mechanism was further investigated by GSEA, GSVA, and other bioinformatic algorithms.

Results: High expression of the KGS signature exhibited a robust association with poorer overall survival (OS) in the TCGA-LUAD dataset (HR: 1.81; 95% CI: 1.35-2.42,  = 0.00011). The association was further corroborated in three external GEO cohorts, including GSE31210 (HR: 3.31; 95% CI: 1.7-6.47,  = 0.00017), GSE72094 (HR: 1.95; 95% CI: 1.34-2.85,  = 0.00057) and GSE26939 (HR: 3.19; 95% CI: 1.74-5.84,  < 0.0001). Interestingly, KGS-high tumors revealed enrichments in TGF-β and WNT-β catenin signaling pathways, exhibited heightened activation of the epithelial-mesenchymal transition (EMT) pathway and proved intensified tumor stemness compared to their KGS-low counterparts. Additionally, KGS-high tumor cells exhibited increased sensitivity to several targeted agents, including gefitinib, erlotinib, lapatinib, and trametinib, in comparison to KGS-low cells.

Conclusion: This study developed a KGS score that independently predicts the prognosis in LUAD. High expression of KGS score, accompanied by upregulation of TGF-β and WNT-β catenin signaling pathways, confers more aggressive EMT and tumor progression.