Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming

Abstract

Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 (EIF4A1) and EIF4A2, in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1, but not EIF4A2, was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1. Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

Targeted in silico characterization of fusion transcripts in tumor and normal tissues via FusionInspector

“…We obtained similar results when applying FusionInspector to the TARGET pediatric cancer cohorts, with a single COSMIC-enriched cluster of fusion occurrences with relatively high fusion expression and 3′-FAR, containing known cancer drivers and yielding a source of additional potential fusion genes for future study. These additional fusions included gene partners PTMA, EIF4A1, and SEPT14, each with known roles in cancer (e.g., Frattini et al., 39 , 60 , 61 Kumar et al., 39 , 60 , 61 and Wu et al. 39 , 60 , 61 ) but yet to be further characterized as pediatric cancer fusion transcripts.…”

“…These additional fusions included gene partners PTMA, EIF4A1, and SEPT14, each with known roles in cancer (e.g., Frattini et al., 39 , 60 , 61 Kumar et al., 39 , 60 , 61 and Wu et al. 39 , 60 , 61 ) but yet to be further characterized as pediatric cancer fusion transcripts.…”

eIF4A1 Is a Prognostic Marker and Actionable Target in Human Hepatocellular Carcinoma

“…Thus, eIF4A1 might represent a novel prognostic marker in this disease. Accordingly, a negative prognostic role of eIF4A1 has been previously detected in other tumor types, such as lung adenocarcinoma [58], clear cell renal carcinoma [59], and gastric cancer [23], among many others.…”

The dark side of mRNA translation and the translation machinery in glioblastoma

“…Dysregulation of eIF4A activity promotes cancer phenotypes such as cell invasion, proliferation, migration, and epithelial-mesenchymal transition in different neoplasia, including lung adenocarcinoma ( Wu et al, 2022 ), breast ( Modelska et al, 2015 ), colorectal ( Li et al, 2017 ), and gastric cancers ( Gao et al, 2020 ) in which eIF4A gene is overexpressed and eIF4A levels associated to poor clinical outcomes. In high-grade gliomas, eIF4A and eIF4H are significantly increased, and their expression level is related to the degree of tumor progression ( Figure 4 ).…”