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.