Cancer-associated fibroblasts secreted miR-103a-3p suppresses apoptosis and promotes cisplatin resistance in non-small cell lung cancer.

Background The cisplatin resistance of non-small cell lung cancer (NSCLC) patients results in low response rate and overall survival rate. Exosomes contribute to pathological processes of multiple cancers. Objective In this study, we explored the function and mechanisms of exosomal miR-103a-3p derived from cancer-associated fibroblast (CAF) in cisplatin resistance in NSCLC. Results MiR-103a-3p was highly expressed in CAFs and CAF exosomes, and exosomal miR-103a-3p derived from CAFs in NSCLC. CAFs exosomes co-cultured with NSCLC cells promoted miR-103a-3p expression both in NSCLC cells and its exosomes. Functional experiments showed that exo-miR-103a-3p derived from CAFs promoted cisplatin resistance and inhibited apoptosis in NSCLC cells. Pumilio2 (Pum2) bound with miR-103a-3p in cytoplasm and nucleus, and facilitated packaging into CAF-derived exosomes in NSCLC cells. Further analysis showed Bak1 was a direct target of miR-103a-3p, and miR-103a-3p accelerated cisplatin resistance in NSCLC cells via Bak1 downregulation. In vivo tumorigenesis assay showed CAF-derived exosomal miR-103a-3p enhanced cisplatin resistance and inhibited cell apoptosis in NSCLC. Conclusion Our study revealed that CAFs-derived exosomal miR-103a-3p promoted cisplatin resistance by suppressing apoptosis via targeting Bak1, which provided a potential therapeutic target for cisplatin resistance in NSCLC.