KLF4 as a Novel Prognostic Biomarker and Its Correlation with Immune Infiltrates in Lung Adenocarcinoma

Abstract

Abstract Background: Improving the treatment of lung adenocarcinoma (LUAD) requires urgent exploration of molecular mechanisms underlying its progression and new prognostic predictors due to low long-term survival rates. Carcinogenesis studies have highlighted the clinical implications of KLF4, a member of the Krüppel-like transcription factor family. In this study, we aimed to investigate the expression of KLF4 in LUAD, assess its correlation with clinicopathological characteristics, prognosis and tumor immune cell infiltration, and analyze its potential advantages as a prognostic marker for LUAD patients. Methods: This study examined KLF4 expression and clinical characteristics in normal and LUAD patients using TCGA and GEO datasets. 25 pairs of LUAD and normal tissues were then validated by IHC. Then we utilized analyses including PPI, GO, KEGG, GSEA and assessment of methylation status, to explore the potential mechanism of KLF4 in LUAD. Differences in the abundance of immune cell infiltration with high and low KLF4 expression were assessed by ssGSEA. Finally, univariate and multivariate Cox regression analysis were performed to construct a nomogram for evaluating the correlation between KLF4 expression and clinical prognosis. Results: KLF4 was downregulated among tumors compared with normal tissue in multiple LUAD cohorts (P < 0.001). KLF4-related genes were then identified through differential analysis, and functional annotation revealed its significant enrichment in the processes of cornification and peptidase activity. GSEA indicated a potential involvement of KLF4 in tumor immunoregulation. Further analysis revealed a significant correlation between the expression of KLF4 and the infiltration levels of neutrophils, mast cells, eosinophils, and NK CD56bright cells (P < 0.001). Additionally, KLF4 in LUAD was found associated with a wide range of immune markers. Notably, higher level of KLF4 significantly reduced prognostic factors including OS, DSS and PFI. Finally, a nomogram incorporating KLF4, pathologic T and N stage, and residual tumor was built and exhibited promising predictive power for assessing the survival outcomes of LUAD patients. Conclusion: High expression of KLF4 is an independent adverse prognostic factor in LUAD, and is strongly associated with aggressive clinical features and unfavorable immune infiltration. Therefore, KLF4 can be used as a novel prognostic biomarker for predicting patient outcomes.