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

Abstract

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.

Significance of platelet adhesion-related genes in colon cancer based on non-negative matrix factorization-based clustering algorithm

“…DUBR, MIR99AHG, PINK1-AS, SGMS1-AS1, LINC01128, and SCAMP1-AS1 were investigated in LUAD. 63 – 68 Furthermore, it was reported that ARHGAP5-AS1 is upregulated in chemoresistant gastric cancer cells and that the knockdown of the lncRNA reverses the resistance. 69 AL031123.2 can be used as a prognostic factor in cervical cancer.…”

Identification of the Key miRNAs and Genes Associated with the Regulation of Non-Small Cell Lung Cancer: A Network-Based Approach

“…Moreover, a bioinformatics integrative analysis carried out on NSCLC by Shao and colleagues, in the year 2017, included only two datasets GSE63459 and GSE36681, which identified some novel miRs as potential biomarkers [ 37 ]. Furthermore, some studies have shown the analysis on NSCLC by constructing the circRNA–miRNA–mRNA network (circRNA: circular RNA) [ 38 , 39 ] or lncRNA–miRNA–mRNA network (lncRNA: long non-coding RNA) [ 40 ], LINC00973-miRNA-mRNA ceRNA (ceRNA: competing endogenous RNA) [ 36 ] but included different datasets altogether (GSE101684 andGSE112214 [ 38 ]; GSE102286, GSE112214 and GSE101929 [ 39 ]; GSE193628 [ 40 ]; GSE27262, GSE89039, GSE101929, GSE40791 and GSE33532 [ 41 ]), besides the given datasets used in our present investigation. Some more published literatures on NSCLC included data patient samples like [ 42 , 43 ].…”

Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions

“…This activates the PI3K/Akt signaling pathway and promotes EGFR-TKI resistance. Another lncRNA, HIF1A-AS2, has been shown to be downregulated by RTKIs, resulting in reduced tumor growth in NSCLC [ 175 ]. HIF1A-AS2 also regulates the expression of specific genes involved in angiogenesis, such as VEGFA, by interacting with specific proteins.…”