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Cancer exosomal microRNAs from gefitinib-resistant lung cancer cells cause therapeutic resistance in gefitinib-sensitive cells

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Abstract

Purpose

Exosomes and their cargo microRNAs play a significant role in various biological processes in cancer. We hypothesized that microRNAs in exosomes secreted by gefitinib-resistant lung cancer cells might induce resistant phenotypes in otherwise gefitinib-sensitive lung cancer cells.

Methods

We isolated exosomes generated by the gefitinib-resistant human lung adenocarcinoma cell line PS-9/ZD. PC-9, which is a gefitinib-sensitive cell line, was treated with the PC-9/ZD exosomes, and these PC-9 cells were analyzed for cell proliferation after treatment with gefitinib. miRNA arrays were analyzed in PC-9 and PC-9/ZD cells, and we isolated microRNAs that were expressed at elevated levels in PC-9/ZD cells. Furthermore, we transfected these microRNAs into PC-9 cells and analyzed the effects on the cells’ sensitivity to gefitinib.

Results

Exosomes isolated from PC-9/ZD cells significantly increased the proliferation of PC-9 cells during gefitinib treatment. A microRNA array analysis showed that miR-564, miR-658, miR-3652, miR-3126-5p, miR-3682-3p and miR-6810-5p were significantly upregulated in PC-9/ZD cells. PC-9 cells transfected with miR-564 or miR-658 showed chemo-resistant phenotypes.

Conclusion

Exosomal miR-564 and miR-658 derived from gefitinib-resistant lung cancer cells induce drug resistance in sensitive cells. Cell-to-cell interaction via exosomal microRNAs may be a novel mechanism and therapeutic target of resistance against gefitinib.

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Acknowledgements

We would like to thank Prof. Kazuto Nishio for providing valuable cell lines for us. We are also grateful to Prof. Akira Iyoda for helpful discussions and comments on the manuscript. This work was supported in part by the grants of Japan Surgical Society Young Researcher Award in 2016.

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Correspondence to Yoko Azuma.

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Azuma, Y., Yokobori, T., Mogi, A. et al. Cancer exosomal microRNAs from gefitinib-resistant lung cancer cells cause therapeutic resistance in gefitinib-sensitive cells. Surg Today (2020). https://doi.org/10.1007/s00595-020-01976-x

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Keywords

  • Lung cancer
  • Gefitinib resistance
  • Cell-to-cell interaction
  • Exosome
  • microRNAs