title: Vav3 is linked to poor prognosis of pancreatic cancers and promotes the motility and invasiveness of pancreatic cancer cells.
abstract: OBJECTIVE
  The aim of this study was to investigate the role of the guanine nucleotide exchange factor Vav3 in the motility and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells.
  
  
  METHODS
  Immunohistochemistry was used to determine whether high Vav3 expression in human PDAC tissues is correlated with poor prognosis. Immunocytochemistry was used to determine the association and intracellular distribution of Vav3, Rac1 and Akt in PDAC cells. Phosphoprotein array analysis was performed to determine the Vav3-associated intracellular signaling pathways. Immunocytochemistry and Matrigel invasion assays were used to examine the effects of Vav3 on the formation of cell protrusions and PDAC cell invasion.
  
  
  RESULTS
  Expression of Vav3 in PDAC tissue was significantly correlated with overall survival. Vav3 was localized in cell protrusions of migrating PDAC cells. Knockdown of Vav3 inhibited the motility and invasiveness of PDAC cells through a decrease in cell protrusions. The levels of active Rac1 or active Akt were not associated with the concentration of Vav3 in cell protrusions. The Vav3-dependent promotion of motility and invasiveness was not modulated by Rac1 or Akt. Additionally, knockdown of Vav3 increased phosphorylated WNK1 in PDAC cells, and knockdown of WNK1 inhibited the motility and invasiveness. This study suggests that Vav3 can be a useful marker for predicting the outcome of patients with PDAC and that Vav3 can promote PDAC cell motility and invasion through association with dephosphorylation of WNK1.
  
  
  CONCLUSIONS
  Vav3 was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and thereby increased the motility and invasiveness of PDAC cells.
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan; Department of Endoscopic Diagnostics and Therapeutics, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan. Electronic address: ktaniuchi@kochi-u.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Taniuchi
authors.affiliation: Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.affiliation: Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Naganuma
authors.affiliation: Department of Surgery, Matsuyama Municipal Hospital, Matsuyama, Ehime 794-0067, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Surgery, Matsuyama Municipal Hospital, Matsuyama, Ehime 794-0067, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Dabanaka
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hanazaki
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan.
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000601:surgery; D002465:Cell Movement / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000032:analysis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000601:surgery; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood; D051567:Proto-Oncogene Proteins c-vav / Q000032:analysis* / Q000235:genetics*; D016019:Survival Analysis; D000076204:WNK Lysine-Deficient Protein Kinase 1; D020830:rac1 GTP-Binding Protein / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D051567:Proto-Oncogene Proteins c-vav; C107953:RAC1 protein, human; C496621:VAV3 protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; D020830:rac1 GTP-Binding Protein
keywords: Cell invasion; Pancreatic cancer; Prognostic factor; Vav protein; With no lysine (K) (WNK)