EIF4A3 stabilizes the expression of lncRNA AGAP2-AS1 to activate cancer-associated fibroblasts via MyD88/NF-κb signaling.

BACKGROUND: Lung cancer (LC) is a fatal malignancy and often accompanied with converting normal fibroblasts to cancer-associated fibroblasts (CAFs). Exosomal lncRNA AGAP2-AS1 has been elucidated to be a potent prognostic factor for LC, while its role in activating CAFs is largely unknown. METHODS: We first extracted exosomes from LC patients and co-cultured them with MRC5 cells to observe the state of MRC5 cells, detect AGAP2-AS1 using real-time quantitative polymerase chain reaction, and then analyze the interaction between EIF4A3 and AGAP2-AS1 using RNA pull down experiments. CCK-8 assay was used to detect cell proliferation. Transwell experiments demonstrated the regulation of MRC5 cells and, finally, the role of MyD88/NF-κB in the downstream mechanism of EIF4A3/AGAP2-AS1 was explored by RNA interference technology and pyrrolidinedithiocarbamic acid inhibition. RESULTS: We demonstrated that exosomes from the LC patients (cancer-exo) notably increased the metastatic ability of MRC-5 cells, promoting the expressions of the CAF biomarkers and lncRNA AGAP2-AS1. Overexpression of lncRNA AGAP2-AS1 prominently activated MRC-5 cells. Moreover, EIF4A3 was upregulated in the cancer-exo-treated MRC-5 cells, and EIF4A3 was verified to bind with lncRNA AGAP2-AS1 to improve its stability. The MyD88/NF-κB signaling pathway was subsequently proved to be positively regulated by lncRNA AGAP2-AS1, and the promotive role of lncRNA AGAP2-AS1 in LC and activating CAFs was confirmed in vivo. CONCLUSIONS: The positive feedback of EIF4A3/AGAP2-AS1/MyD88/NF-κB signaling pathway contributed to the activation of CAFs and exacerbated LC in turn, revealing a novel regulatory axis underlying LC.