Na + /H + exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma

// Yosuke Ariyoshi 1, * , Atsushi Shiozaki 1, * , Daisuke Ichikawa 1 , Hiroki Shimizu 1 , Toshiyuki Kosuga 1 , Hirotaka Konishi 1 , Shuhei Komatsu 1 , Hitoshi Fujiwara 1 , Kazuma Okamoto 1 , Mitsuo Kishimoto 2 , Yoshinori Marunaka 3, 4 , Eigo Otsuji 1 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan 2 Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan 3 Department of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science,Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan 4 Japan Institute for Food Education and Health, St. Agnes’ University, Kyoto 602-8013, Japan * These authors contributed equally to this work Correspondence to: Atsushi Shiozaki, email: shiozaki@koto.kpu-m.ac.jp Keywords: esophageal squamous cell carcinoma, Na + /H + exchanger 1, epithelial-mesenchymal transition, prognosis, Notch signaling Received: March 29, 2016      Accepted: October 21, 2016      Published: November 26, 2016 ABSTRACT Na + /H + exchanger 1 (NHE1) is a plasma membrane transporter that controls intracellular pH and regulates apoptosis and invasion in various cancer cells. However, the function of NHE1 in esophageal squamous cell carcinoma (ESCC) cells and the relationship between the expression of NHE1 and prognosis of ESCC remain unclear. We found that the knockdown of NHE1 in ESCC cells inhibited apoptosis and promoted cell proliferation, migration, and invasion and showed increases in Snail, β-catenin, and activation of PI3K-AKT signaling, which was consistent with the results obtained from microarrays. Microarrays results suggested that the knockdown of NHE1 suppressed Notch signaling pathway. An immunohistochemical investigation of 61 primary ESCC samples revealed that NHE1 was expressed at higher levels in well-differentiated tumors. The 5-year survival rate was poorer in the NHE1 low group (57.0%) than in the NHE1 high group (82.8%). Multivariate analyses revealed that the weak expression of NHE1 was associated with shorter postoperative survival (hazard ratio 3.570, 95% CI 1.291-11.484, p = 0.0135).We herein demonstrated that the suppression of NHE1 in ESCC may enhance malignant potential by mediating PI3K-AKT signaling and EMT via Notch signaling, and may be related to a poor prognosis in patients with ESCC.