title: HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer.
abstract: OBJECTIVE
  To investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells.
  
  
  METHODS
  Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments.
  
  
  RESULTS
  In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.
  
  
  CONCLUSIONS
  HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Yiseul
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Youngsun
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Pyo
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Bo Gun
authors.initials: BG
authors.lastname: Jang
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Douk Ho
authors.initials: DH
authors.lastname: Hwang
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Yiseul Choi, Jinju Park, Youngsun Choi, Woo Ho Kim, Byung Lan Lee, Department of Tumor Biology, Cancer Research Institute, Seoul National Universit, College of Medicine, Seoul 110-799, South Korea.
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D025461:Feedback, Physiological; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Gastric cancer; HER2; Metastatic potential; Protein kinase B; c-Jun N-terminal kinase