title: NEDD9 crucially regulates TGF-β-triggered epithelial-mesenchymal transition and cell invasion in prostate cancer cells: involvement in cancer progressiveness.
abstract: BACKGROUND
  NEDD9 is one of the Crk-associated substrate (Cas) family proteins that mediate downstream signaling processes including cytoskeletal organization, cell-cycle and tumorigenesis. While NEDD9 plays a crucial role in epithelial-mesenchymal transition (EMT), the functional mechanism underlying NEDD9-mediated EMT in prostate cancer (PCa) remains uncertain.
  
  
  METHODS
  The expression levels of NEDD9 and its downstream molecules in PC-3, LNCaP, and VCaP cells exposed to transforming growth factor-β (TGF-β) were determined by western blotting. The invasion of these cells with ectopic overexpression of NEDD9 or silencing of NEDD9 expression was measured by transwell invasion assay. Human tissue samples comprising 45 PCa specimens and ten specimens of normal prostatic tissue were used for immunohistochemical (IHC) analysis of NEDD9 expression.
  
  
  RESULTS
  Both NEDD9 and its downstream signaling molecules associated with EMT were strongly induced by TGF-β in PCa cells. PC-3 cells with stable overexpression of NEDD9 had a mesenchymal phenotype and significantly enhanced cell invasion, despite their decreased cell proliferation. Knockdown of endogenous NEDD9 expression completely diminished TGF-β-triggered tumor invasion in several PCa cell lines. The IHC data revealed a significant positive correlation between the NEDD9 staining score and tumor aggressiveness (e.g., Gleason grade, serum PSA level). The NEDD9 staining score in primary PCa with bone metastasis was significantly higher than that in PCa without metastasis.
  
  
  CONCLUSIONS
  NEDD9 may be a key mediator involved in TGF-β-mediated EMT and cell motility in PCa cells and a novel target in the treatment of metastatic PCa and prevention of spread of localized PCa cells to other organs.
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Morimoto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Nitta
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kawashima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D010750:Phosphoproteins / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000633:toxicity*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta
keywords: NEDD9; TGF-β; epithelial-mesenchymal transition; prostate cancer