miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway

Han,Jing; Zhao,Fengyi; Zhang,Jing; Zhu,Haizhen; Ma,Hu; Li,Xuetao; Peng,Lina; Sun,Jianguo; Chen,Zhengtang

doi:10.3892/ijo.2016.3401

miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway

Authors:
- Jing Han
- Fengyi Zhao
- Jing Zhang
- Haizhen Zhu
- Hu Ma
- Xuetao Li
- Lina Peng
- Jianguo Sun
- Zhengtang Chen
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Affiliations: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China, Department of Oncology, 401 Hospital of the People's Liberation Army, Qingdao, Shandong 266071, P.R. China, Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China, Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China
Published online on: February 19, 2016 https://doi.org/10.3892/ijo.2016.3401
Pages: 1855-1867
Copyright: © Han et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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