eIF4A1 enhances p70S6K mRNA translation and promotes nuclear β-catenin levels to augment stemness and metastasis in gastric cancer cells.

Abstract

Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide, with tumor stemness and metastasis driving poor prognosis. This study explores the role of eukaryotic translation initiation factor 4A1 (eIF4A1) in promoting these aggressive features in GC. eIF4A1 was found to be upregulated in stem-like (CD133+) GC cells. Gain- and loss-of-function experiments in cell lines, combined with xenograft, chemically induced, and organoid models, demonstrated that eIF4A1 enhanced cancer stemness, cell mobility, tumorigenesis, and metastasis. Mechanistically, eIF4A1 selectively promotes p70 ribosomal S6 kinase (p70S6K) mRNA translation, leading to increased glycogen synthase kinase 3 beta (GSK3β) phosphorylation, elevated nuclear β-catenin accumulation, and subsequent transcriptional activation of eIF4A1 via the β-catenin/transcription factor 7-like 2 (TCF7L2) complex, thus forming a positive feedback loop. Clinically, high expression of eIF4A1, p70S6K, and TCF7L2 correlates with unfavorable prognosis in GC patients. These findings highlight eIF4A1 as a key regulator of stemness and metastasis through a novel translational feedback mechanism, suggesting potential therapeutic targeting to disrupt tumor progression.