Open Access

Interleukin‑6 identified as an important factor in hypoxia‑ and aldehyde dehydrogenase‑based gefitinib adaptive resistance in non‑small cell lung cancer cells

  • Authors:
    • Shi‑Min An
    • Hui‑Min Lei
    • Xu‑Ping Ding
    • Fan Sun
    • Chun Zhang
    • Ya‑Bin Tang
    • Hong‑Zhuan Chen
    • Ying Shen
    • Liang Zhu
  • View Affiliations

  • Published online on: July 20, 2017     https://doi.org/10.3892/ol.2017.6613
  • Pages: 3445-3454
  • Copyright: © An et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gefitinib resistance and relapse of the disease were the greatest challenges facing clinical therapy of non‑small‑cell lung cancer (NSCLC). Of note, regarding the hypoxia condition in solid tumor tissues in vivo, roles of hypoxia in gefitinib adaptive resistance and its association with lung cancer stem cells (LCSCs) have not been fully elucidated. In the present study, the role of hypoxia in gefitinib adaptive resistance and its association with aldehyde dehydrogenase (ALDH)‑based LCSC gefitinib resistance were comparatively studied using RNA‑sequencing (RNA‑seq) technology. Co‑treatment of PC9 cells with gefitinib and hypoxia (1% O2) significantly enhanced adaptive resistance compared with gefitinib or hypoxia treatment alone. An ALDEFLUOR assay demonstrated that there was a significant increase of ALDH expression level in hypoxia and gefitinib co‑treated PC9 cells, in addition to a higher ratio of G0/G1 quiescent cell enrichment and acquisition of epithelial‑mesenchymal transition. RNA‑seq analysis revealed that interleukin‑6 (IL‑6) is an important common factor in hypoxia and ALDH‑based gefitinib resistance, supported by inflammation‑associated tumor necrosis factor, nuclear factor‑κB and Janus kinase‑signal transducer and activator of transcription signaling pathway enrichment. Furthermore, exposure of PC9 and HCC827 cells to IL‑6 increased gefitinib adaptive resistance. Consequently, IL‑6 expression level was a poor prognostic marker for patients with NSCLC and adenocarcinoma. Thus, targeting IL‑6 combined with tyrosine kinase inhibitor treatment may be promising in NSCLC clinical therapy in the future.
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September-2017
Volume 14 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Spandidos Publications style
An SM, Lei HM, Ding XP, Sun F, Zhang C, Tang YB, Chen HZ, Shen Y and Zhu L: Interleukin‑6 identified as an important factor in hypoxia‑ and aldehyde dehydrogenase‑based gefitinib adaptive resistance in non‑small cell lung cancer cells. Oncol Lett 14: 3445-3454, 2017.
APA
An, S., Lei, H., Ding, X., Sun, F., Zhang, C., Tang, Y. ... Zhu, L. (2017). Interleukin‑6 identified as an important factor in hypoxia‑ and aldehyde dehydrogenase‑based gefitinib adaptive resistance in non‑small cell lung cancer cells. Oncology Letters, 14, 3445-3454. https://doi.org/10.3892/ol.2017.6613
MLA
An, S., Lei, H., Ding, X., Sun, F., Zhang, C., Tang, Y., Chen, H., Shen, Y., Zhu, L."Interleukin‑6 identified as an important factor in hypoxia‑ and aldehyde dehydrogenase‑based gefitinib adaptive resistance in non‑small cell lung cancer cells". Oncology Letters 14.3 (2017): 3445-3454.
Chicago
An, S., Lei, H., Ding, X., Sun, F., Zhang, C., Tang, Y., Chen, H., Shen, Y., Zhu, L."Interleukin‑6 identified as an important factor in hypoxia‑ and aldehyde dehydrogenase‑based gefitinib adaptive resistance in non‑small cell lung cancer cells". Oncology Letters 14, no. 3 (2017): 3445-3454. https://doi.org/10.3892/ol.2017.6613