NOX4 overexpression is a poor prognostic factor in patients undergoing curative esophagectomy for esophageal squamous cell carcinoma

Background: Nox4 has been associated with tumor progression in various types of malignancies. This study aimed to evaluate the importance of the expression of Nox4 in patients undergoing curative esophagectomy for esophageal squamous cell carcinoma. Methods: We reviewed retrospectively 121 patients with esophageal squamous cell carcinoma who had undergone a curative esophagectomy, including 67 patients with overexpression and 54 patients with low expression of Nox4 as evaluated by immunohistochemical analysis. In addition, 2 esophageal squamous cell carcinoma cell lines, TE11 and KYSE270, were treated with the Nox4 inhibitor GKT-137831 to explore the expression of Nox4, cell proliferative activity, and selected downstream pathways in these esophageal squamous cell carcinoma cell lines by Western blot analysis. Results: Univariate analysis showed that T1-2 status, absence of nodal metastasis, and low Nox4 expression were associated with greater disease-free survival (P = .001) and overall survival (P < .001), and Nox4 overexpression was an independent prognostic factor of worse disease-free survival and overall survival (P = .013 and P = .007, respectively). The esophageal squamous cell carcinoma cell lines treated with the Nox4 inhibitor GKT-137831 showed decreased cell proliferation in a dose-dependent manner (P < .01). Western blot analysis demonstrated that expression of AKT, phosphorylated AKT, mammalian target of rapamycin, and phosphorylated mammalian target of rapamycin were less in esophageal squamous cell carcinoma cells treated with the Nox4 inhibitor (P < .01). Conclusion: This study suggests that Nox4 overexpression is a poor prognostic factor for patients with esophageal squamous cell carcinoma undergoing curative esophagectomy.