CAFs-Derived Exosomal miRNA-130a Confers Cisplatin Resistance of NSCLC Cells Through PUM2-Dependent Packaging
Authors Zhang T, Zhang P, Li HX
Received 13 July 2020
Accepted for publication 29 September 2020
Published 25 January 2021 Volume 2021:16 Pages 561—577
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Linlin Sun
Tao Zhang,1 Ping Zhang,2 Hong-Xia Li3
1Department of Tuberculosis, Linyi People’s Hospital, Linyi, Shandong 276034, People’s Republic of China; 2Reproductive Medicine, Linyi People’s Hospital, Linyi, Shandong 276034, People’s Republic of China; 3Endoscopic Room, Linyi Chest Hospital, Linyi, Shandong 276034, People’s Republic of China
Correspondence: Hong-Xia Li
Endoscopic Room, Linyi Chest Hospital, No. 233 Fenghuang Avenue, Hedong District, Linyi, Shandong 276034, People’s Republic of China
Purpose: Chemoresistance is a significant barrier to the treatment and management of non-small 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 CAFs-conditioned medium significantly promoted the survival rate of NSCLC cells after cisplatin treatment. Additionally, CAFs-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.
Keywords: chemoresistance, non-small cell lung cancer, cancer-associated fibroblasts, exosome, miRNA-130a, pumilio homolog 2
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