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ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC

  • Authors:
    • Xiang Cao
    • Xin‑Ming Chen
    • Wei‑Zhang Xiao
    • Ben Li
    • Bo Zhang
    • Qiong Wu
    • Qun Xue
  • View Affiliations / Copyright

    Affiliations: Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
    Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 573-582
    |
    Published online on: December 15, 2020
       https://doi.org/10.3892/ijmm.2020.4819
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Abstract

Deoxyribonucleic acid (DNA) epigenetic modification has been linked to specific sequences of CpG islands and plays roles in the progression of lung cancer. In this study, it was found that peroxiredoxin‑5 (PRDX5) was highly expressed in non‑small cell lung cancer (NSCLC) tissues; however, its specific regulatory mechanisms and functions in NSCLC remain unknown. The present study therefore explored the regulatory mechanism of PRDX5 under conditions of oxidative stress (OS) in NSCLC. The results revealed that 79 of 121 NSCLC patients exhibited demethylation in the PRDX5 promoter region, which was related to the tumor, node and metastasis (TNM) stage (P=0.027). PRDX5 messenger ribonucleic acid (mRNA) expression positively correlated with the demethylation status of the promoter region. The results of bisulfite sequencing polymerase chain reaction (BSP) revealed lower demethylation frequencies in H1299 cells treated with 0 µM H2O2, but maximum demethylation following treatment with 100 µM H2O2. Using chromatin immunoprecipitation (ChIP) and luciferase detection assays, the effective binding of STAT3 to the transcriptional binding sites of the PRDX5 promoter region was confirmed (2 sites confirmed: Site 1, ‑444 to ‑434 bp; and site 4, ‑1,417 to ‑1,407 bp). STAT3 knockdown significantly decreased the protein expression of PRDX5, while the overexpression of STAT3 significantly increased the protein levels of PRDX5. When PRDX5 was overexpressed in lung cancer cells under conditions of OS, the levels of the epithelial‑mesenchymal transition (EMT) biomarkers, E‑cadherin and vimentin, were significantly decreased and increased, respectively. By contrast, PRDX5 knockdown resulted in significantly increased E‑cadherin and decreased vimentin protein expression levels. Ultimately, when PRDX5‑small interfering RNA (siRNA) or pcDNA3.1‑PRDX5 expression vector were constructed and transfected into H1299 cells pre‑treated with 100 µM H2O2, the nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) signaling pathway was inhibited or activated. All these results suggested that the reactive oxygen species (ROS)‑mediated hypomethylation of PRDX5 enhanced STAT3 binding affinity with the promoter region, and resulted in the promotion of cell migration and invasion, as well as in the activation of the Nrf2 signaling pathway in NSCLC. The demethylation status of the PRDX5 promoter may thus be used as an epigenetic biomarker in NSCLC. STAT3/PRDX5 signaling may also prove to be a potential strategy for the treatment of this type of cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Cao X, Chen XM, Xiao WZ, Li B, Zhang B, Wu Q and Xue Q: ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC. Int J Mol Med 47: 573-582, 2021.
APA
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., & Xue, Q. (2021). ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC. International Journal of Molecular Medicine, 47, 573-582. https://doi.org/10.3892/ijmm.2020.4819
MLA
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., Xue, Q."ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC". International Journal of Molecular Medicine 47.2 (2021): 573-582.
Chicago
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., Xue, Q."ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC". International Journal of Molecular Medicine 47, no. 2 (2021): 573-582. https://doi.org/10.3892/ijmm.2020.4819
Copy and paste a formatted citation
x
Spandidos Publications style
Cao X, Chen XM, Xiao WZ, Li B, Zhang B, Wu Q and Xue Q: ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC. Int J Mol Med 47: 573-582, 2021.
APA
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., & Xue, Q. (2021). ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC. International Journal of Molecular Medicine, 47, 573-582. https://doi.org/10.3892/ijmm.2020.4819
MLA
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., Xue, Q."ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC". International Journal of Molecular Medicine 47.2 (2021): 573-582.
Chicago
Cao, X., Chen, X., Xiao, W., Li, B., Zhang, B., Wu, Q., Xue, Q."ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC". International Journal of Molecular Medicine 47, no. 2 (2021): 573-582. https://doi.org/10.3892/ijmm.2020.4819
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