Open Access

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

  • Authors:
    • Wenwen Du
    • Lin Sun
    • Ting Liu
    • Jianjie Zhu
    • Yuanyuan Zeng
    • Yang Zhang
    • Xueting Wang
    • Zeyi Liu
    • Jian‑An Huang
  • View Affiliations

  • Published online on: April 8, 2020     https://doi.org/10.3892/or.2020.7579
  • Pages: 185-195
  • Copyright: © Du et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gefitinib is currently the preferred treatment for non‑small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)‑activating mutation. However, some patients gradually develop acquired resistance after receiving treatment. In addition to secondary T790M mutation, the remaining mechanisms contributing to non‑T790M mutations need to be explored. In the present study, NSCLC‑derived HCC827 and PC‑9 cells and the corresponding gefitinib‑resistant cell lines (HCC827GR and PC9GR) were utilized. Next‑generation DNA sequencing was performed on the HCC827GR and PC9GR cells. Under AXL receptor tyrosine kinase (AXL) knockdown or miR‑625‑3p overexpressing conditions, a cell growth inhibition assay was performed to evaluate gefitinib sensitivity. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Moreover, we also carried out western blot analysis to detect the altered downstream signaling pathway. Our study revealed markedly decreased miR‑625‑3p expression in the HCC827GR cell line, while its overexpression partly reversed gefitinib resistance. Integrated analysis based on Targetscan website showed that AXL can be potentially targeted by miR‑625‑3p and we further verified the hypothesis via dual‑luciferase reporter assays. Mechanistic analysis revealed that TGF‑β1‑induced EMT may contribute to the miR‑625‑3p/AXL axis‑mediated gefitinib resistance. Our data demonstrated that miR‑625‑3p contributes to the acquired resistance of gefitinib, which may provide novel insight to combat resistance to EGFR‑TKIs.
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July 2020
Volume 44 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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APA
Du, W., Sun, L., Liu, T., Zhu, J., Zeng, Y., Zhang, Y. ... Huang, J. (2020). The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer. Oncology Reports, 44, 185-195. https://doi.org/10.3892/or.2020.7579
MLA
Du, W., Sun, L., Liu, T., Zhu, J., Zeng, Y., Zhang, Y., Wang, X., Liu, Z., Huang, J."The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer". Oncology Reports 44.1 (2020): 185-195.
Chicago
Du, W., Sun, L., Liu, T., Zhu, J., Zeng, Y., Zhang, Y., Wang, X., Liu, Z., Huang, J."The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer". Oncology Reports 44, no. 1 (2020): 185-195. https://doi.org/10.3892/or.2020.7579