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miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression

Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly...

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Autores principales: Liu, Bing-Jie, Li, Fang-Fang, Xie, Yun-Xia, Fan, Chong-Yuan, Liu, Wen-Jing, Qiu, Jian-Ge, Jiang, Bing-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836598/
https://www.ncbi.nlm.nih.gov/pubmed/35163707
http://dx.doi.org/10.3390/ijms23031785
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author Liu, Bing-Jie
Li, Fang-Fang
Xie, Yun-Xia
Fan, Chong-Yuan
Liu, Wen-Jing
Qiu, Jian-Ge
Jiang, Bing-Hua
author_facet Liu, Bing-Jie
Li, Fang-Fang
Xie, Yun-Xia
Fan, Chong-Yuan
Liu, Wen-Jing
Qiu, Jian-Ge
Jiang, Bing-Hua
author_sort Liu, Bing-Jie
collection PubMed
description Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future.
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spelling pubmed-88365982022-02-12 miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression Liu, Bing-Jie Li, Fang-Fang Xie, Yun-Xia Fan, Chong-Yuan Liu, Wen-Jing Qiu, Jian-Ge Jiang, Bing-Hua Int J Mol Sci Article Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future. MDPI 2022-02-04 /pmc/articles/PMC8836598/ /pubmed/35163707 http://dx.doi.org/10.3390/ijms23031785 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Bing-Jie
Li, Fang-Fang
Xie, Yun-Xia
Fan, Chong-Yuan
Liu, Wen-Jing
Qiu, Jian-Ge
Jiang, Bing-Hua
miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title_full miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title_fullStr miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title_full_unstemmed miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title_short miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
title_sort mir-196a upregulation contributes to gefitinib resistance through inhibiting gltp expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836598/
https://www.ncbi.nlm.nih.gov/pubmed/35163707
http://dx.doi.org/10.3390/ijms23031785
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