title: miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway.
abstract: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR‑223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR‑223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133+, which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR‑223 expression in PC9/ER and PC9/CD133+ cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR‑223 stably transfected PC9/ER and PC9/CD133+ cells. However, the sensitivity of PC9/ER and PC9/CD133+ cells to erlotinib was partially restored, after overexpression of miR‑223 in those cells. Similar results were also observed in vivo. Furthermore, miR‑223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR‑223 transfected cells. Our findings indicated that downregulation of miR‑223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133+ cells, may be responsible for the resistance of PC9/ER and PC9/CD133+ cells to erlotinib, suggesting that miR‑223 is a potential therapeutic target for overcoming EGFR-TKIs resistance.
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Fengyi
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Oncology, 401 Hospital of the People's Liberation Army, Qingdao, Shandong 266071, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Ma
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Peng
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
authors.affiliation: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
authors.forename: Zhengtang
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C000597236:IGF1R protein, human; C525067:MIR223, human