title: Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1.
abstract: OBJECTIVE
  We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1.
  
  
  METHODS
  Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues.
  
  
  RESULTS
  In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues.
  
  
  CONCLUSIONS
  Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sue Youn
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.affiliation: Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yiseul
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea ; Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Pyo
authors.affiliation: Department of Anatomy, Dankook University School of Medicine, Cheonan, Korea.
authors.forename: Young Bok
authors.initials: YB
authors.lastname: Yoo
authors.affiliation: Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea ; Tumour Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea ; Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071161:Forkhead Box Protein O1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D056564:Sirtuin 1 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Angiogenesis modulating agents; Human FOXO1 protein; Human SIRT1 protein; Stomach neoplasms