title: Glutamate acid decarboxylase 1 promotes metastasis of human oral cancer by β-catenin translocation and MMP7 activation.
abstract: BACKGROUND
  Glutamate decarboxylase 1 (GAD1), a rate-limiting enzyme in the production of γ-aminobutyric acid (GABA), is found in the GABAergic neurons of the central nervous system. Little is known about the relevance of GAD1 to oral squamous cell carcinoma (OSCC). We investigated the expression status of GAD1 and its functional mechanisms in OSCCs.
  
  
  METHODS
  We evaluated GAD1 mRNA and protein expressions in OSCC-derived cells using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunoblotting analyses. To assess the critical functions of GAD1, i.e., cellular proliferation, invasiveness, and migration, OSCC-derived cells were treated with the shRNA and specific GAD1 inhibitor, 3-mercaptopropionic acid (3-MPA). GAD1 expression in 80 patients with primary OSCCs was analyzed and compared to the clinicopathological behaviors of OSCC.
  
  
  RESULTS
  qRT-PCR and immunoblotting analyses detected frequent up-regulation of GAD1 in OSCC-derived cells compared to human normal oral keratinocytes. Suppression of nuclear localization of β-catenin and MMP7 secretion was observed in GAD1 knockdown and 3-MPA-treated cells. We also found low cellular invasiveness and migratory abilities in GAD1 knockdown and 3-MPA-treated cells. In the clinical samples, GAD1 expression in the primary OSCCs was significantly (P < 0.05) higher than in normal counterparts and was correlated significantly (P < 0.05) with regional lymph node metastasis.
  
  
  CONCLUSIONS
  Our data showed that up-regulation of GAD1 was a characteristic event in OSCCs and that GAD1 was correlated with cellular invasiveness and migration by regulating β-catenin translocation and MMP7 activation. GAD1 might play an important role in controlling tumoral invasiveness and metastasis in oral cancer.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Department of Clinical Molecular Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. kasamatsua@faculty.chiba-u.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Koyama
authors.forename: Chonji
authors.initials: C
authors.lastname: Fukumoto
authors.forename: Yukinao
authors.initials: Y
authors.lastname: Kouzu
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higo
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Endo-Sakamoto
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ogawara
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
mesh_terms: D015097:3-Mercaptopropionic Acid / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004789:Enzyme Activation; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000473:pathology; D009361:Neoplasm Invasiveness; D021381:Protein Transport; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D015097:3-Mercaptopropionic Acid; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1