let‑7 and miR‑17 promote self‑renewal and drive gefitinib resistance in non‑small cell lung cancer

Yin,Jun; Hu,Weimin; Pan,Lei; Fu,Wenfan; Dai,Lu; Jiang,Zeyong; Zhang,Feng; Zhao,Jian

doi:10.3892/or.2019.7197

let‑7 and miR‑17 promote self‑renewal and drive gefitinib resistance in non‑small cell lung cancer

Authors:
- Jun Yin
- Weimin Hu
- Lei Pan
- Wenfan Fu
- Lu Dai
- Zeyong Jiang
- Feng Zhang
- Jian Zhao
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Affiliations: Department of Chest Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China, Department of Abdominal Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China
Published online on: June 12, 2019 https://doi.org/10.3892/or.2019.7197
Pages: 495-508
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Epidermal growth factor receptor‑tyrosinase kinase inhibitor (EGFR‑TKI) resistance represents a major obstacle in the therapy of non‑small cell lung cancer (NSCLC), and the underlying molecular mechanisms are unknown. In this study, it was found that let‑7 family expression was downregulated and miR‑17 family expression was upregulated in gefitinib‑resistant PC9/GR cells compared with gefitinib‑sensitive PC9 cells. The downregulation of let‑7 and upregulation of miR‑17 have significant clinical relevance to gefitinib resistance in NSCLC. Moreover, it was shown that downregulation of let‑7 and upregulation of miR‑17 promoted resistance to gefitinib by regulating the self‑renewal capability of NSCLC cells. In addition, let‑7 participated in the maintenance of stem cell characteristics by regulating the target gene MYC, and miR‑17 participated in regulation of the cell cycle by regulating the target gene CDKN1A. In NSCLC cells, low expression of let‑7 increased MYC expression to help maintain the undifferentiated status, and high expression of miR‑17 decreased CDKN1A expression to help maintain the proliferative potential. Thus, both let‑7 and miR‑17 promoted self‑renewal, which is typical of stem cell‑like characteristics and resulted in gefitinib resistance. Therefore, this study demonstrated that let‑7 and miR‑17 were involved in the regulation of EGFR‑TKI resistance, and could be used as predictive biomarkers of EGFR‑TKI resistance in NSCLC.

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