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Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines.

ABSTRACT: BACKGROUND:Osimertinib (AZD9291), a third-generation EGFR-tyrosine kinase inhibitor, can effectively prolong survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations, particularly T790M mutations; however, acquired resistance to AZD9291 is inevitable, thus exploration of the targets of resistance is urgent. METHODS:Considering the important role of circular RNAs (circRNAs) in cancers, we established AZD9291-resistant NSCLC cell lines (H1975/AZDR and HCC827/AZDR) and used microarray analysis to determine the circRNA expression profiles of the cells. The H1975/AZDR and HCC827/AZDR cell lines were induced by gradually increasing the drug concentration. CircRNA microarray expression profiles were obtained from H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells and validated by quantitative reverse transcription PCR. Expression data were analyzed bioinformatically. RESULTS:The H1975/AZDR and HCC827/AZDR cell lines were successfully established. The half-maximal inhibitory concentration and the invasion ability of H1975/AZDR and HCC827/AZDR cells were significantly enhanced. The proliferation rates of H1975/AZDR and HCC827/AZDR were much lower than H1975 and HCC827. Microarray analysis identified 15?504 circRNAs differentially expressed in H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells. Among them, 7966 were upregulated and 7538 were downregulated more than two-fold. We predicted the possible miRNAs of the top dysregulated circRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer-related pathways. CONCLUSION:Our results reveal that circRNAs may play a role in NSCLC AZD9291 resistance and might be a promising molecular target candidate for gene therapy.

SUBMITTER: Chen T

PROVIDER: S-EPMC6449233 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines.

Chen Tianxiang T Luo Jizhuang J Gu Yu Y Huang Jia J Luo Qingquan Q Yang Yunhai Y

Thoracic cancer 20190318 4

<h4>Background</h4>Osimertinib (AZD9291), a third-generation EGFR-tyrosine kinase inhibitor, can effectively prolong survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations, particularly T790M mutations; however, acquired resistance to AZD9291 is inevitable, thus exploration of the targets of resistance is urgent.<h4>Methods</h4>Considering the important role of circular RNAs (circRNAs) in cancers, we established AZD9291-resistant NSCLC cell lines (H1975/AZDR and HCC827/AZDR) ...[more]

PMID: 30883029

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Project description:Background: Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used to treat EGFR mutation-positive patients with non-small cell lung cancer (NSCLC). However, the efficacy of gefitinib is limited by the development of acquired resistance. Studies have shown that circular RNAs (circRNAs) are involved in the acquired resistance to many anticancer agents. However, the expression profiles and functions of circRNAs in gefitinib resistance in NSCLC are poorly understood so far. Methods: In this study, circRNA expression profiling was explored in two gefitinib-resistant NSCLC cell lines (HCC827/GR and PC9/GR) and their parental sensitive cells (HCC827 and PC9) using high-throughput RNA sequencing. Quantitative real-time PCR (qRT-PCR) was used to confirm the expression of selected differentially expressed circRNAs. Bioinformatic tools including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), network analysis, and Kaplan-Meier plotter database were used to predict the functions and pathways of these differentially expressed circRNAs. Results: We identified 46 and 56 differentially expressed circRNAs in HCC827/GR and PC9/GR cell lines, respectively, compared with those in their parental cell lines. Gene ontology and KEGG pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions. We found that hsa_circ_0000567 was consistently up-regulated, and hsa_circ_0006867 was consistently down-regulated in two resistant cell lines. We further used hsa_circ_0000567 and hsa_circ_0006867 as key circRNAs to construct circRNA-miRNA-mRNA networks. Several target mRNAs of these two circRNAs had been shown to significantly associate with the overall survival of patients with lung cancer. Conclusions: In this study, we generated the comprehensive expression and functional profiles of the differentially expressed circRNAs between gefitinib-resistant and -sensitive NSCLC cells, and showed that dysregulation of circRNAs might play an important role in the development of acquired resistance to gefitinib in NSCLC.

Dataset Information

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines.

Publications

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines.

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