Tumor-derived exosomal miR-21-5p mediates lung fibroblasts activation via TNFAIP3/NF-kB signaling to promote non-small cell lung cancer cell migration and invasion

MicroRNAs (miRNAs) have been recognized as significant mediators in non-small cell lung cancer (NSCLC). However, their particular effects on NSCLC remain largely unknown. In addition, fibroblasts are essential components of the tumor microenvironment (TME) and play significant roles in tumor development. It has been also reported that exosomes can mediate the communication between tumor cells and fibroblasts in TME. However, the role of extracellular miR-21 in the intercellular communication of tumor cells and fibroblasts remains elusive. The differentially expressed miRNAs between NSCLC and normal tissues were identified by screening the Gene Expression Omnibus (dataset, GSE63805) and The Cancer Genome Atlas databases using R language software. The bioinformatics analysis results showed that compared with normal tissues, miR-21-5p was upregulated in lung cancer tissues, while the increased expression levels of miR-21-5p were associated with worse survival rate in patients with NSCLC. Additionally, exosomes could deliver miR-21-5p from NSCLC cells to lung fibroblasts, thus enhancing the levels of miR-21-5p in fibroblasts. Furthermore, the results demonstrated that tumor necrosis factor α induced protein 3 (TNFAIP3) was a direct target of miR-21-5p in NSCLC cells. These results suggested that exosomal miR-21-5p derived from NSCLC cells could activate lung fibroblasts via targeting TNFAIP3-mediated nuclear factor κB (NF-κB) signaling. Most importantly, exosomal miR-21-5p could facilitate fibroblast activation, which in turn could enhance the migration and epithelial-mesenchymal transition of NSCLC cells. Overall, the findings of the present study revealed that NSCLC cell-derived exosomal miR-21-5p could mediate lung fibroblast activation via the TNFAIP3/NF-kB signaling pathway to promote NSCLC cell migration and invasion. Therefore, targeting exosomal miR-21-5p could provide a potential strategy for the prevention and treatment of NSCLC.