title: Elevated Na+/H+exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells.
abstract: Cancer cells can migrate as collectives during invasion and/or metastasis; however, the precise molecular mechanisms of this form of migration are less clear compared with single cell migration following epithelial-mesenchymal transition. Elevated Na+/H+exchanger1 (NHE1) expression has been suggested to have malignant roles in a number of cancer cell lines and in vivo tumor models. Furthermore, a metastatic human head and neck squamous cell carcinoma (HNSCC) cell line (SASL1m) that was isolated based on its increased metastatic potential also exhibited higher NHE1 expression than its parental line SAS. Time-lapse video recordings indicated that both cell lines migrate as collectives, although with different features, e.g., SASL1m was much more active and changed the direction of migration more frequently than SAS cells, whereas locomotive activities were comparable. SASL1m cells also exhibited higher invasive activity than SAS in Matrigel invasion assays. shRNA-mediated NHE1 knockdown in SASL1m led to reduced locomotive and invasive activities, suggesting a critical role for NHE1 in the collective migration of SASL1m cells. SASL1m cells also exhibited a higher metastatic rate than SAS cells in a mouse lymph node metastasis model, while NHE1 knockdown suppressed in vivo SASL1m metastasis. Finally, elevated NHE1 expression was observed in human HNSCC tissue, and Cariporide, a specific NHE1 inhibitor, reduced the invasive activity of SASL1m cells, implying NHE1 could be a target for anti-invasion/metastasis therapy.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: kaminota28@gmail.com.
authors.forename: Teppei
authors.initials: T
authors.lastname: Kaminota
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: hajime-y@m.ehime-u.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shiota
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: iamnoricotta.eupp74@gmail.com.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: susiehanji02i@yahoo.co.jp.
authors.forename: Haruna
authors.initials: H
authors.lastname: Yaguchi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: z401039b@mails.cc.ehime-u.ac.jp.
authors.forename: Yui
authors.initials: Y
authors.lastname: Kirino
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: kntr753@gmail.com.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: isseiiron@gmail.com.
authors.forename: Issei
authors.initials: I
authors.lastname: Tetsumura
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: sanada_tomo@yahoo.co.jp.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Sanada
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: ugumorit@m.ehime-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Ugumori
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: jtanaka@m.ehime-u.ac.jp.
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ehime University Medical School, 454, Shitsukawa, To-on, Ehime, 791-0295, Japan. Electronic address: nhato@m.ehime-u.ac.jp.
authors.forename: Naohito
authors.initials: N
authors.lastname: Hato
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D059008:Time-Lapse Imaging / Q000379:methods; D014183:Transplantation, Heterologous
chemical_list: D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers
keywords: Actin cytoskeleton; Collective cell migration; Head and neck squamous cell carcinoma; Lymph node metastasis; NHE1