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Surg Today. 2020 Feb 12. doi: 10.1007/s00595-020-01976-x. [Epub ahead of print]

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

Author information

1
Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi, 371-8511, Japan. yoko.azuma@med.toho-u.ac.jp.
2
Division of Chest Surgery, Department of Surgery, Toho University School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan. yoko.azuma@med.toho-u.ac.jp.
3
Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi, 371-8511, Japan.
4
Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), 3-39-22 Showa-machi, Maebashi, 371-8511, Japan.

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.

KEYWORDS:

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

PMID:
32052182
DOI:
10.1007/s00595-020-01976-x

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