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NADPH Oxidase 2 Has a Crucial Role in Cell Cycle Progression of Esophageal Squamous Cell Carcinoma

  • Translational Research
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

NADPH oxidases (NOXs) are transmembrane proteins that generate reactive oxygen species. Recent studies have reported that NOXs are involved in tumor progression in various cancers. However, the expression and role of NOX2 in esophageal squamous cell carcinoma (ESCC) remain unclear. This study aimed to clarify the pathophysiologic role of NOX2 in patients with ESCC and cell lines.

Methods

Two human ESCC cell lines (TE5 and KYSE170) were used for NOX2 transfection experiments, and the effects on cell proliferation, cell cycle, cell motility, and cell survival were analyzed. An mRNA microarray analysis was also performed to assess gene expression profiles. Additionally, NOX2 immunohistochemistry was performed on 130 primary ESCC tumor samples to assess the prognostic value of NOX2 in patients with ESCC.

Results

NOX2 depletion significantly inhibited cell proliferation with the G0/G1 arrest and resulted in apoptosis in two cell lines. Microarray analysis revealed a strong relationship between NOX2 gene expression and the signaling pathway of cell cycle regulation by the B-cell translocation gene 2 (BTG2) family, including BTG2, CCNE2, E2F1, and CDK2 genes. Immunohistochemical staining revealed that high NOX2 protein expression was significantly associated with deeper tumor invasion and selected as one of the independent prognostic factors associated with the 5-year OS rate in patients with ESCC.

Conclusions

NOX2 expression in ESCC cells affects tumorigenesis, especially cell cycle progression via the BTG2-related signaling pathway, as well as the prognosis of patients with ESCC. NOX2 may be a novel biomarker and therapeutic target for ESCC.

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Acknowledgements

The present study was supported by a Grant-in-Aid for Young Scientists (Grant No. 20K17609) from the Japan Society for the Promotion of Science.

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Author notes

  1. Hiroki Shimizu and Keita Katsurahara have contributed equally to this work.

Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Hiroki Shimizu MD, Keita Katsurahara MD, Hiroyuki Inoue MD, Atsushi Shiozaki MD, Toshiyuki Kosuga MD, Michihiro Kudou MD, Tomohiro Arita MD, Hirotaka Konishi MD, Shuhei Komatsu MD, Hitoshi Fujiwara MD & Eigo Otsuji MD

  2. Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yukiko Morinaga MD & Eiichi Konishi MD

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  1. Hiroki Shimizu MD
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Correspondence to Atsushi Shiozaki MD.

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Shimizu, H., Katsurahara, K., Inoue, H. et al. NADPH Oxidase 2 Has a Crucial Role in Cell Cycle Progression of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 29, 8677–8687 (2022). https://doi.org/10.1245/s10434-022-12384-5

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