title: Loss of FOXO1 promotes gastric tumour growth and metastasis through upregulation of human epidermal growth factor receptor 2/neu expression.
abstract: BACKGROUND
  The biological significance of FOXO1, a member of the forkhead box O transcription factor family, in gastric cancer (GC) remains unclear. The present study provides direct evidence of the role of FOXO1 in tumour growth and metastasis of GC in relation to human epidermal growth factor receptor 2 (HER2).
  
  
  METHODS
  The expressions of FOXO1 and HER2 were modulated in GC cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by stable transfections. The effects of transfection on GC phenotypes were evaluated in vitro and in animal models. In addition, the relationship between FOXO1 and HER2 was analysed using GC clinical specimens, cell lines and xenografts.
  
  
  RESULTS
  FOXO1 silencing in GC cells increased colony formation and mesenchymal transition in vitro, as well as tumour growth and metastasis in nude mice, whereas HER2 silencing induced the opposite results.. Furthermore, an inverse relationship between FOXO1 and HER2 was found in clinical specimens of GC, GC cells and GC xenograft tumours. Although a negative crosstalk between these two molecules was shown, double knockdown of both FOXO1 and HER2 in GC cells revealed that HER2 silencing reversed the FOXO1 shRNA-induced migration and invasion even without the FOXO1 restoration.
  
  
  CONCLUSIONS
  Our results indicate that loss of FOXO1 promotes GC growth and metastasis by upregulating HER2 expression and that the HER2 expression is more critical to the induction of GC cell metastasis. The present study provides evidence that the FOXO1/HER2 pathway may regulate GC progression in a subgroup of GC patients.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Tumour Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Yong Joon
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, South Korea.
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Pyo
authors.affiliation: Department of Pathology, Jeju National University Hospital, Jeju 690-767, South Korea.
authors.forename: Bo Gun
authors.initials: BG
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea.|Tumour Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 110-799, South Korea.|Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; C085126:FOXO1 protein, human; C508053:ERBB2 protein, human