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

Abstract

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.

Distinct roles of CD244 expression in cancer diagnosis and prognosis: A pan-cancer analysis

“…Further research and validation are needed in each tumor to study the relationship between CD244 and the biological processes of EMT, differentiation, invasion, hypoxia, and DNA repair. The enrichment analysis of GO and KEGG pathways has been proved to predict and analyze the roles of essential genes in an organism's survival [ 50 ]. Our results revealed that CD244 is involved in the biological processes of the natural killer cell mediated cytotoxicity, the immune response activating cell surface receptor signaling pathway, the antigen receptor mediated signaling pathway, and the T cell receptor signaling pathway.…”

Long non-coding RNAs in non-small cell lung cancer: implications for EGFR-TKI resistance

“…Different RNA transcripts that have the same miRNA response elements (MREs) and constitute a competitive relationship can act as competitive endogenous RNAs (ceRNAs), the so-called miRNA sponges ( Tay et al, 2014 ). In recent years, there is accumulating evidence suggesting that lncRNAs and their constituent ceRNA networks are implicated with EGFR-TKI resistance of NSCLC ( Kong et al, 2020 ; Wang T. et al, 2021 ). Many lncRNAs that act as ceRNAs to regulate EGFR-TKI resistance in NSCLC have been mentioned above.…”

Panel of miR-150 and linc00673, regulators of CCR6/CCL20 may serve as non-invasive diagnostic marker of non-small cell lung cancer

“…Recently published data show that lncRNAs can interact with miRNAs 19 . It was recently revealed that long non-coding RNAs (lncRNAs) can pose endogenous competitors of miRNAs, and serve as specific “miRNA sponges” by possessing miRNA binding sequences, which results in blocking its function 20 , 21 .…”