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Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer

BACKGROUND: The gefitinib resistance mechanism in non-small cell lung cancer (NSCLC) remains unclear, albeit exosomal circular RNA (circRNA) is known to possibly play a vital role in it. METHODS: We employed high-throughput sequencing techniques to detect the expressions of exosomal circRNA both in...

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Autores principales: Wei, Si-Liang, Ye, Jing-Jing, Sun, Li, Hu, Lei, Wei, Yuan-Yuan, Zhang, Da-Wei, Xu, Meng-Meng, Fei, Guang-He
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10316567/
https://www.ncbi.nlm.nih.gov/pubmed/37394466
http://dx.doi.org/10.1186/s12935-023-02974-y
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author Wei, Si-Liang
Ye, Jing-Jing
Sun, Li
Hu, Lei
Wei, Yuan-Yuan
Zhang, Da-Wei
Xu, Meng-Meng
Fei, Guang-He
author_facet Wei, Si-Liang
Ye, Jing-Jing
Sun, Li
Hu, Lei
Wei, Yuan-Yuan
Zhang, Da-Wei
Xu, Meng-Meng
Fei, Guang-He
author_sort Wei, Si-Liang
collection PubMed
description BACKGROUND: The gefitinib resistance mechanism in non-small cell lung cancer (NSCLC) remains unclear, albeit exosomal circular RNA (circRNA) is known to possibly play a vital role in it. METHODS: We employed high-throughput sequencing techniques to detect the expressions of exosomal circRNA both in gefitinib-resistant and gefitinib-sensitive cells in this study. The circKIF20B expression was determined in serum exosomes and tissues of patients by qRT-PCR. The structure, stability, and intracellular localization of circKIF20B were verified by Sanger sequencing, Ribonuclease R (RNase R)/actinomycin D (ACTD) treatments, and Fluorescence in situ hybridization (FISH). The functions of circKIF20B were investigated by 5-Ethynyl-20-deoxyuridine (EdU), flow cytometry, Cell Counting Kit-8 (CCK-8), oxygen consumption rate (OCR), and xenograft model. Co-culture experiments were performed to explore the potential ability of exosomal circKIF20B in treating gefitinib resistance. The downstream targets of circKIF20B were determined by luciferase assay, RNA pulldown, and RNA immunoprecipitation (RIP). RESULTS: We found that circKIF20B was poorly expressed in the serum exosomes of gefitinib-resistant patients (n = 24) and the tumor tissues of patients with NSCLC (n = 85). CircKIF20B was negatively correlated with tumor size and tumor stage. Decreasing circKIF20B was found to promote gefitinib resistance by accelerating the cell cycle, inhibiting apoptosis, and enhancing mitochondrial oxidative phosphorylation (OXPHOS), whereas increasing circKIF20B was found to restore gefitinib sensitivity. Mechanistically, circKIF20B is bound to miR-615-3p for regulating the MEF2A and then altering the cell cycle, apoptosis, and mitochondrial OXPHOS. Overexpressing circKIF20B parental cells can restore sensitivity to gefitinib in the recipient cells by upregulating the exosomal circKIF20B expression. CONCLUSIONS: This study revealed a novel mechanism of circKIF20B/miR-615-3p/MEF2A signaling axis involving progression of gefitinib resistance in NSCLC. Exosomal circKIF20B is expected to be an easily accessible and alternative liquid biopsy candidate and potential therapeutic target in gefitinib-resistant NSCLC. GRAPHICAL ABSTRACT: SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02974-y.
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spelling pubmed-103165672023-07-04 Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer Wei, Si-Liang Ye, Jing-Jing Sun, Li Hu, Lei Wei, Yuan-Yuan Zhang, Da-Wei Xu, Meng-Meng Fei, Guang-He Cancer Cell Int Research BACKGROUND: The gefitinib resistance mechanism in non-small cell lung cancer (NSCLC) remains unclear, albeit exosomal circular RNA (circRNA) is known to possibly play a vital role in it. METHODS: We employed high-throughput sequencing techniques to detect the expressions of exosomal circRNA both in gefitinib-resistant and gefitinib-sensitive cells in this study. The circKIF20B expression was determined in serum exosomes and tissues of patients by qRT-PCR. The structure, stability, and intracellular localization of circKIF20B were verified by Sanger sequencing, Ribonuclease R (RNase R)/actinomycin D (ACTD) treatments, and Fluorescence in situ hybridization (FISH). The functions of circKIF20B were investigated by 5-Ethynyl-20-deoxyuridine (EdU), flow cytometry, Cell Counting Kit-8 (CCK-8), oxygen consumption rate (OCR), and xenograft model. Co-culture experiments were performed to explore the potential ability of exosomal circKIF20B in treating gefitinib resistance. The downstream targets of circKIF20B were determined by luciferase assay, RNA pulldown, and RNA immunoprecipitation (RIP). RESULTS: We found that circKIF20B was poorly expressed in the serum exosomes of gefitinib-resistant patients (n = 24) and the tumor tissues of patients with NSCLC (n = 85). CircKIF20B was negatively correlated with tumor size and tumor stage. Decreasing circKIF20B was found to promote gefitinib resistance by accelerating the cell cycle, inhibiting apoptosis, and enhancing mitochondrial oxidative phosphorylation (OXPHOS), whereas increasing circKIF20B was found to restore gefitinib sensitivity. Mechanistically, circKIF20B is bound to miR-615-3p for regulating the MEF2A and then altering the cell cycle, apoptosis, and mitochondrial OXPHOS. Overexpressing circKIF20B parental cells can restore sensitivity to gefitinib in the recipient cells by upregulating the exosomal circKIF20B expression. CONCLUSIONS: This study revealed a novel mechanism of circKIF20B/miR-615-3p/MEF2A signaling axis involving progression of gefitinib resistance in NSCLC. Exosomal circKIF20B is expected to be an easily accessible and alternative liquid biopsy candidate and potential therapeutic target in gefitinib-resistant NSCLC. GRAPHICAL ABSTRACT: SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-023-02974-y. BioMed Central 2023-07-02 /pmc/articles/PMC10316567/ /pubmed/37394466 http://dx.doi.org/10.1186/s12935-023-02974-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wei, Si-Liang
Ye, Jing-Jing
Sun, Li
Hu, Lei
Wei, Yuan-Yuan
Zhang, Da-Wei
Xu, Meng-Meng
Fei, Guang-He
Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title_full Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title_fullStr Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title_full_unstemmed Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title_short Exosome-derived circKIF20B suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
title_sort exosome-derived circkif20b suppresses gefitinib resistance and cell proliferation in non-small cell lung cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10316567/
https://www.ncbi.nlm.nih.gov/pubmed/37394466
http://dx.doi.org/10.1186/s12935-023-02974-y
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