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

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.