Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC

• Published in: Frontiers in genetics Vol. 13; p. 851391
• Main Authors: Ding, Dandan, Zhang, Jufeng, Luo, Zhiming, Wu, Huazhen, Lin, Zexiao, Liang, Weicheng, Xue, Xingyang
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 29.04.2022
• Subjects: drug resistance; EGFR-TKIs; Genetics; LINC01128; long non-coding RNA; lung cancer-diagnosis; EGFR-TKIs; LINC01128; long non-coding RNA; drug resistance; lung cancer-diagnosis
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2022.851391

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas how they regulate EGFR-TKI resistance remains unclear. In this study, we examined gene expression using the microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. A total of 45 DE-lncRNAs associated with overall survival and 1799 target DE-mRNAs were employed to construct a core lncRNA–miRNA–mRNA network to illustrate underlying molecular mechanisms of how EGFR-TKI resistance occurs in NSCLC. We found that target DE-mRNAs were mainly enriched in pathways involved in EGFR-TKI resistance, especially the target DE-mRNAs regulated by LINC01128 were significantly enriched in the PI3K/Akt signaling pathway, where the synergy of these target DE-mRNAs may play a key role in EGFR-TKI resistance. In addition, downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. Furthermore, signaling reactions caused by the downregulation of PTEN would activate the PI3K/Akt signaling pathway, which may lead to EGFR-TKI resistance. In addition, a survival analysis indicated the low expression of LINC01128, and PTEN is closely related to poor prognosis in lung adenocarcinoma (LUAD). Therefore, the LINC01128/miR-25-3p/PTEN axis may promote EGFR-TKI resistance via the PI3K/Akt signaling pathway, which provides new insights into the underlying molecular mechanisms of drug resistance to EGFR-TKIs in NSCLC. In addition, our study sheds light on developing novel therapeutic approaches to overcome EGFR-TKI resistance in NSCLC.