title: Na+/H+ exchanger 1 has tumor suppressive activity and prognostic value in esophageal squamous cell carcinoma.
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.
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ariyoshi
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichikawa
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kosuga
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Komatsu
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kishimoto
authors.affiliation: Department of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science,Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.|Japan Institute for Food Education and Health, St. Agnes' University, Kyoto 602-8013, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Marunaka
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D000074082:Sodium-Hydrogen Exchanger 1 / Q000235:genetics / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1
keywords: Na+/H+ exchanger 1; Notch signaling; epithelial-mesenchymal transition; esophageal squamous cell carcinoma; prognosis