title: A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer.
abstract: Underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in cancer cells are diverse and cell type specific. Although both HIF-1alpha and AKT (protein kinase B) have been implicated in gastric tumor promotion and angiogenesis, it remains unclear whether HIF-1 mediates the role of AKT in terms of promoting vascular endothelial growth factor (VEGF) expression. The present study was performed to investigate the correlation between HIF-1alpha activation and AKT activation in gastric cancer using human gastric cancer specimens, in vitro cell experiments and in vivo animal experiments. Immunohistochemistry performed on tissue array slides containing 268 surgical specimens of gastric carcinomas showed immunoreactivity for HIF-1alpha in 29% of samples. Moreover, HIF-1alpha was positively associated with phosphorylated AKT (pAKT) (P = 0.002) or VEGF (P = 0.002), and the immunoreactivities of pAKT and VEGF were positively correlated (P < 0.001). Western blot analysis and reverse transcription-polymerase chain reaction in cell experiments revealed that the over-expression of constitutively active AKT (CA-AKT) promotes the expressions of HIF-1alpha protein and VEGF messenger ribonucleic acid in Seoul national university (SNU)-216 and SNU-668 gastric cancer cells under normoxic conditions, whereas kinase-dead mutant of AKT down-regulated these expressions under the same conditions. Xenografts in nude mice derived from stable gastric cancer cells over-expressing CA-AKT showed higher tumor incidence, larger tumor volumes, higher microvessel density and stronger HIF-1alpha immunoreactivity than those derived from vector control cells. Thus, we propose that the hypoxia-independent promotion of the AKT-HIF-1alpha-VEGF pathway contributes, at least in part, to gastric cancer tumorigenesis and angiogenesis.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Jieun
authors.initials: J
authors.lastname: Jung
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Jihyen
authors.initials: J
authors.lastname: Kim
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Chung
authors.forename: Mee Soo
authors.initials: MS
authors.lastname: Chang
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Nam
mesh_terms: D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D017931:DNA Primers; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt