title: Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer.
abstract: BACKGROUND
  Phosphatase of regenerating liver-3 (PRL-3) has deserved attention as a crucial molecule in the multiple steps of metastasis. In the present study, we examined the mechanisms regulating PRL-3 expression, and assessed the clinical potential of PRL-3-targeted therapy in gastric cancer.
  
  
  METHODS
  PRL-3 genomic amplification was analyzed using quantitative-polymerase chain reaction and/or fluorescence in situ hybridization in 77 primary gastric tumors. The anticancer activity of PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) treatment was evaluated against cancer cells with different genetic and expression status.
  
  
  RESULTS
  PRL-3 genomic amplification was closely concordant with high level of its protein expression in cell lines, and was found in 20% (8/40) among human primary tumors with its expression, which were all stage III/IV disease (40%, 8/20), but in none (0/37) among those without expression. Additionally, PRL-3 genomic amplification was associated with metastatic lymph node status, leading to advanced stage and thereby poor outcomes in patients with lymph node metastasis (P = 0.021). PRL-3 small interfering RNA robustly repressed metastatic properties, including cell proliferation, invasion, and anchorage-independent colony formation. Although neither PRL-3 genomic amplification nor expression level was responsible for the sensitivity to PRL-3 inhibitor treatment, the inhibitor showed dose-dependent anticancer efficacy, and remarkably induced apoptosis on all the tested cell lines with PRL-3 expression.
  
  
  CONCLUSIONS
  We have for the first time, demonstrated that PRL-3 genomic amplification is one of the predominant mechanisms inducing its expression, especially in more advanced stage, and that PRL-3-targeted therapy may have a great potential against gastric cancer with its expression.
authors.affiliation: Department of Surgery, Kitasato University Hospital, Kitasato 1-15-1, Sagamihara 228-8555, Kanagawa, Japan. sp9y9tq9@piano.ocn.ne.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Ooki
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamashita
authors.forename: Shiro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sakuramoto
authors.forename: Natsuya
authors.initials: N
authors.lastname: Katada
authors.forename: Mina
authors.initials: M
authors.lastname: Waraya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimiya
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D001597:Benzylidene Compounds; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012236:Rhodanine; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases