CAFs-Derived Exosomal miRNA-130a Confers Cisplatin Resistance of NSCLC Cells Through PUM2-Dependent Packaging

Purpose: Chemoresistance is a significant barrier to the treatment and management of nonsmall cell lung cancer (NSCLC). Exosomes play an essential role in intercellular communication. Understanding the mechanism underlying the role of tumor stroma, especially cancer-associated fibroblasts (CAFs), during chemoresistance would significantly contribute to the clinical application of chemotherapy agents. Results: In this study, we demonstrated that NSCLC-derived CAFs were innately resistant to cisplatin treatment and CAF s-conditioned medium significantly promoted the survival rate of NSCLC cells after cisplatin treatment. Additionally, CAF s-derived exosomes were taken up by NSCLC cells. Moreover, exosomal miRNA-130a was transferred from CAFs to recipient NSCLC cells and knockdown of miRNA-130a reversed the effect of CAFs-derived exosomes during chemoresistance of NSCLC cells. Furthermore, pumilio homolog 2 (PUM2), a RNA-binding protein, mediated the packaging of miRNA-130a into exosomes. The overexpression and knockdown of PUM2 promoted and inhibited tumor growth of xenograft mice, respectively. Conclusion: Taken together, these results suggest that CAFs-derived exosomes confer cisplatin resistance of NSCLC cells through transferring miRNA-130a and that PUM2 is a critical factor for packaging miRNA-130a into exosomes. This study indicates that CAFs-derived exosomal miRNA-130a may be a potential therapeutic target for cisplatin resistance in NSCLC.

Automated summary

This study demonstrated that CAFs-derived exosomes confer cisplatin resistance to NSCLC cells by transferring miRNA-130a, with PUM2 identified as a critical factor in packaging miRNA-130a into the exosomes. The results suggest that CAFs-derived exosomal miRNA-130a may be a potential therapeutic target for cisplatin resistance in NSCLC.