miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway
Journal
Molecular therapy. Nucleic acids
Journal Volume
22
Date Issued
2020-12-04
Author(s)
Liu, Yi-Nan
Tsai, Meng-Feng
Chang, Tzu-Hua
Gow, Chien-Hung
Wang, Hsin-Yi
Abstract
Although patients with non-small cell lung cancer harboring activating mutations in the epidermal growth factor receptor (EGFR) show good clinical response to EGFR tyrosine kinase inhibitors (TKIs), patients eventually develop acquired resistance. Previous studies have shown that several microRNAs (miRNAs) are involved in EGFR TKI resistance. Here, we aimed to investigate whether miR-146b-5p sensitizes the EGFR TKI-resistant lung cancer cells. Clinical analysis showed that miR-146b-5p expression in lung cancer cells isolated from pleural effusions of treatment-naive patients was significantly higher than that after acquiring resistance to EGFR TKI treatment. Ectopic expression of miR-146b-5p in EGFR TKI-resistant cells enhanced EGFR TKI-induced apoptosis. The same results were observed in EGFR-dependent and -independent osimertinib-resistant primary cancer cells (PE3479 and PE2988). Mechanically, miR-146b-5p suppressed nuclear factor κB (NF-κB) activity and NF-κB-related IL-6 and IL-8 production by targeting IRAK1. A negative correlation was observed between miR-146b-5p and IRAK1 in clinical specimens. In rescue experiments, restoration of IRAK1 expression reversed the effects of miR-146b-5p on EGFR TKI sensitivity and recovered NF-κB-regulated IL-6 and IL-8 production. In conclusion, miR-146b-5p/IRAK1/NF-κB signaling is important in promoting EGFR TKI resistance, and miR-146b-5p may be a useful tool for overcoming EGFR TKI resistance.
Subjects
EGFR TKI; IRAK1; NF-κB; NSCLC; microRNA; resistance
SDGs
Other Subjects
caspase 3; epidermal growth factor receptor kinase inhibitor; immunoglobulin enhancer binding protein; interleukin 1 receptor associated kinase 1; interleukin 6; interleukin 8; messenger RNA; microRNA; microRNA 125b 3p; microRNA 139 5p; microRNA 146b 5p; microRNA 193b; microRNA 221; microRNA 223a 5p; microRNA 29c; osimertinib; tumor necrosis factor receptor associated factor 6; unclassified drug; apoptosis; Article; cancer cell; cancer resistance; cell proliferation; controlled study; cytokine production; down regulation; drug sensitivity; ectopic expression; exon; human; human cell; immunoblotting; malignant pleura effusion; molecularly targeted therapy; non small cell lung cancer; PC-9/IR cell line; pleura effusion; primary tumor; priority journal; upregulation
Type
journal article