Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor

Background: Tyrosine kinase inhibitors that act against epidermal growth factor receptor (EGFR) show strong efficacy against non-small cell lung cancer (NSCLC) involving mutated EGFRs. However, most such patients eventually develop resistance to EGFR-TKIs. Numerous researches have reported that mess...

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Autores principales:	Ting Wang, Chengliang Yang, Bing Li, Ying Xing, Jian Huang, Yangping Zhang, Shanshan Bu, Hong Ge
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	EGFR-TKI resistance NSCLC competitive endogenous RNA network Genetics QH426-470
Acceso en línea:	https://doaj.org/article/10c69bcdf9e64502a7c16d0cab50806a
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spelling	oai:doaj.org-article:10c69bcdf9e64502a7c16d0cab50806a2021-11-12T05:16:53ZIdentification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor1664-802110.3389/fgene.2021.758591https://doaj.org/article/10c69bcdf9e64502a7c16d0cab50806a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.758591/fullhttps://doaj.org/toc/1664-8021Background: Tyrosine kinase inhibitors that act against epidermal growth factor receptor (EGFR) show strong efficacy against non-small cell lung cancer (NSCLC) involving mutated EGFRs. However, most such patients eventually develop resistance to EGFR-TKIs. Numerous researches have reported that messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) may be involved in EGFR-TKI resistance, but the comprehensive expression profile and competitive endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in EGFR-TKI resistance of NSCLC are incompletely known. We aimed to define a ceRNA regulatory network linking mRNAs and non-coding RNAs that may mediate this resistance.Methods: Using datasets GSE83666, GSE75309 and GSE103352 from the Gene Expression Omnibus, we identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs differentially expressed between NSCLC cells that were sensitive or resistant to EGFR-TKIs. The potential biological functions of the corresponding differentially expressed genes were analyzed based KEGG pathways. We combined interactions among lncRNAs, miRNAs and mRNAs in the RNAInter database with KEGG pathways to generate transcriptional regulatory ceRNA networks associated with NSCLC resistance to EGFR-TKIs. Kaplan-Meier analysis was used to assess the ability of core ceRNA regulatory sub-networks to predict the progression-free interval and overall survival of NSCLC. The expression of two core ceRNA regulatory sub-networks in NSCLC was validated by quantitative real-time PCR.Results: We identified 8,989 lncRNAs, 1,083 miRNAs and 3,191 mRNAs that were differentially expressed between patients who were sensitive or resistant to the inhibitors. These DEGs were linked to 968 biological processes and 31 KEGG pathways. Pearson analysis of correlations among the DEGs of lncRNAs, miRNAs and mRNAs identified 12 core ceRNA regulatory sub-networks associated with resistance to EGFR-TKIs. The two lncRNAs ABTB1 and NPTN with the hsa-miR-150–5p and mRNA SERPINE1 were significantly associated with resistance to EGFR-TKIs and survival in NSCLC. These lncRNAs and the miRNA were found to be down-regulated, and the mRNA up-regulated, in a resistant NSCLC cell line relative to the corresponding sensitive cells.Conclusion: In this study, we provide new insights into the pathogenesis of NSCLC and the emergence of resistance to EGFR-TKIs, based on a lncRNA-miRNA-mRNA network.Ting WangChengliang YangBing LiYing XingJian HuangYangping ZhangShanshan BuHong GeFrontiers Media S.A.articleEGFR-TKIresistanceNSCLCcompetitive endogenous RNAnetworkGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGFR-TKI resistance NSCLC competitive endogenous RNA network Genetics QH426-470
spellingShingle	EGFR-TKI resistance NSCLC competitive endogenous RNA network Genetics QH426-470 Ting Wang Chengliang Yang Bing Li Ying Xing Jian Huang Yangping Zhang Shanshan Bu Hong Ge Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
description	Background: Tyrosine kinase inhibitors that act against epidermal growth factor receptor (EGFR) show strong efficacy against non-small cell lung cancer (NSCLC) involving mutated EGFRs. However, most such patients eventually develop resistance to EGFR-TKIs. Numerous researches have reported that messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) may be involved in EGFR-TKI resistance, but the comprehensive expression profile and competitive endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in EGFR-TKI resistance of NSCLC are incompletely known. We aimed to define a ceRNA regulatory network linking mRNAs and non-coding RNAs that may mediate this resistance.Methods: Using datasets GSE83666, GSE75309 and GSE103352 from the Gene Expression Omnibus, we identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs differentially expressed between NSCLC cells that were sensitive or resistant to EGFR-TKIs. The potential biological functions of the corresponding differentially expressed genes were analyzed based KEGG pathways. We combined interactions among lncRNAs, miRNAs and mRNAs in the RNAInter database with KEGG pathways to generate transcriptional regulatory ceRNA networks associated with NSCLC resistance to EGFR-TKIs. Kaplan-Meier analysis was used to assess the ability of core ceRNA regulatory sub-networks to predict the progression-free interval and overall survival of NSCLC. The expression of two core ceRNA regulatory sub-networks in NSCLC was validated by quantitative real-time PCR.Results: We identified 8,989 lncRNAs, 1,083 miRNAs and 3,191 mRNAs that were differentially expressed between patients who were sensitive or resistant to the inhibitors. These DEGs were linked to 968 biological processes and 31 KEGG pathways. Pearson analysis of correlations among the DEGs of lncRNAs, miRNAs and mRNAs identified 12 core ceRNA regulatory sub-networks associated with resistance to EGFR-TKIs. The two lncRNAs ABTB1 and NPTN with the hsa-miR-150–5p and mRNA SERPINE1 were significantly associated with resistance to EGFR-TKIs and survival in NSCLC. These lncRNAs and the miRNA were found to be down-regulated, and the mRNA up-regulated, in a resistant NSCLC cell line relative to the corresponding sensitive cells.Conclusion: In this study, we provide new insights into the pathogenesis of NSCLC and the emergence of resistance to EGFR-TKIs, based on a lncRNA-miRNA-mRNA network.
format	article
author	Ting Wang Chengliang Yang Bing Li Ying Xing Jian Huang Yangping Zhang Shanshan Bu Hong Ge
author_facet	Ting Wang Chengliang Yang Bing Li Ying Xing Jian Huang Yangping Zhang Shanshan Bu Hong Ge
author_sort	Ting Wang
title	Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
title_short	Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
title_full	Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
title_fullStr	Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
title_full_unstemmed	Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor
title_sort	identification of lncrna–mirna–mrna networks linked to non-small lung cancer resistance to inhibitors of epidermal growth factor receptor
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/10c69bcdf9e64502a7c16d0cab50806a
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Identification of lncRNA–miRNA–mRNA Networks Linked to Non-small Lung Cancer Resistance to Inhibitors of Epidermal Growth Factor Receptor

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