Hypoxia‑inducible factor-1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib

Jin,Qian; Zhou,Jianying; Xu,Xianrong; Huang,Feihua; Xu,Weihua

doi:10.3892/ol.2019.10025

Hypoxia‑inducible factor-1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib

Authors:
- Qian Jin
- Jianying Zhou
- Xianrong Xu
- Feihua Huang
- Weihua Xu
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Affiliations: Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Respiratory Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
Published online on: February 7, 2019 https://doi.org/10.3892/ol.2019.10025
Pages: 4034-4043

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Abstract

The majority of patients with non‑small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations inevitably progress in stage despite an initial substantial and rapid response to EGFR‑tyrosine kinase inhibitors (EGFR‑TKIs). Previous research indicates that hypoxia may be associated with resistance to EGFR‑TKIs in EGFR mutation‑positive NSCLC. Therefore, the present study regulated the activity of hypoxia‑inducible factor-1 (HIF‑1) signaling pathway to observe if it is able to alter the sensitivity of lung cancer cells to gefitinib. The present study selected 3‑(5'‑hydroxymethyl‑2'‑furyl)‑1‑benzylindazole (YC‑1) and dimethyloxalylglycine (DMOG) as a HIF‑1 signaling pathway inhibitor and activator, respectively, on HCC827 cells. Cells were incubated with different treatments for different durations: A blank control, DMOG, gefitinib, or DMOG and gefitinib combined, for 36 and 48 h; and then a blank control, YC‑1, gefitinib, or YC‑1 and gefitinib combined, for 16 and 28 h. A western blot analysis assay was performed to evaluate the protein expression levels of HIF‑1α and phosphorylated hepatocyte growth factor receptor (p‑MET), an MTT assay was used to determine cell proliferation, a colony formation assay was used to investigate the colony‑forming ability and a wound healing assay was used to test the cell migration ability. Additionally, Pearson's correlation analysis was used to evaluate the correlation between p‑Met and HIF‑1α expression levels. Finally, it was identified that gefitinib and DMOG combined notably improve the growth and cell migration ability of HCC827 cells, compared with gefitinib alone. When gefitinib and YC‑1 were combined, the inhibiting effect on the growth and cell migration ability of HCC827 cells was substantially enhanced, compared with the control cells. Pearson's correlation analysis revealed that the p‑Met expression level had a strong positive correlation with HIF‑1α expression levels. Thus, it was concluded that the HIF‑1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib. The positive correlation between p‑Met and HIF‑1α expression levels may be the underlying mechanism of the HIF‑1 signaling pathway influencing the sensitivity of HCC827 cells to gefitinib.

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