Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for advanced non-small-cell lung cancer (NSCLC) patients. However, acquired resistance to EGFR-TKIs is widely detected across the world, and the exact mechanisms have not been fully demonstrated until now. This study aimed to examine the role of miR-214 in the acquired resistance to erlotinib in NSCLC, and elucidate the underlying mechanisms. qRT-PCR assay detected higher miR-214 expression in the plasma of NSCLC patients with acquired EGFR-TKI resistance than prior to EGFR-TKI therapy, and in the generated erlotinib-resistant HCC827 (HCC827/ER) cells than in HCC827 cells. Bioinformatics analysis and dual-luciferase reporter assay indentified LHX6 as a direct target gene of miR-214, and LHX6 expression was detected to be down-regulated in erlotinib-resistant HCC827 cells. Transwell invasion assay revealed that overexpressing LHX6 reversed the increase in the invasive ability of HCC827 cells induced by miR-214 overexpression, and the CRISPR-Cas9 system-mediated LHX6 knockdown reversed the reduction in the invasion of erlotinib-resistant HCC827 cells caused by miR-214 down-regulation. The results of the present study demonstrate that down-regulation of miR-214 may reverse acquired resistance to erlotinib in NSCLC through mediating its direct target gene LHX6 expression.
Highlights
Lung cancer is the most common tumor and the leading cause of cancer-related mortality worldwide[1]
Of the seven non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutation enrolled in this study, who developed disease progression and had acquired EGFR-tyrosine kinase inhibitors (TKIs) resistance, the plasma was sampled for quantifying miR-214 expression. qRT-PCR assay showed higher relative miR-214 expression level in the plasma of NSCLC patients with acquired EGFR-TKI resistance than prior to EGFR-TKI therapy (5.63 ± 2.33 vs. 3.31 ± 1.24, P = 0.398) (Fig. 1a)
Our findings demonstrate that the elevated miR-214 expression may correlate with the acquired EGFR-TKI resistance in both HCC827 cells and NSCLC patients
Summary
Lung cancer is the most common tumor and the leading cause of cancer-related mortality worldwide[1]. It is reported that EGFR-TKIs, such as erlotinib and gefitinib, achieve a median progression-free survival (PFS) of 8 to 16 months in the treatment of EGFR-mutant NSCLC patients, and acquired drug resistance may develop[8]. MicroRNA (miRNA), a class of small non-coding RNA molecules containing 19 to 23 nucleotides that serve as key mediators in post-transcriptional gene regulation, has been found to be involved in the acquired resistance to EGFR-TKIs in NSCLC12–14. It is hypothesized that miR-214 may mediate the resistance of EGFR-mutant NSCLC to TKIs through mediating cancer cell apoptosis-associated target genes. To test this hypothesis, this study was designed to examine the role of miR-214 in the acquired resistance to erlotinib in NSCLC, and elucidate the underlying mechanisms
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