title: Significance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma.
abstract: OBJECTIVE
  Hypoxia is known to be a prevalent stress stimulus and increases the transcription of vascular endothelial growth factor (VEGF) mediated by hypoxia inducible factor-1alpha (HIF-1alpha). We investigated the role of phosphatidyl inositol-3 OH kinase (PI3K)-Akt signaling in the regulation of HIF-1alpha and VEGF expression in human gastric adenocarcinoma.
  
  
  METHODS
  The growth-inhibitory and apoptosis-inducing effects of the LY294002 PI3K inhibitor were analyzed in four gastric cancer cell lines and in vivo. The regulatory mechanism of VEGF and HIF-1alpha expression under hypoxic conditions was examined in the cell cultures. In 88 gastric cancer tissue samples, phosphorylated Akt and VEGF expression were analyzed immunohistochemically.
  
  
  RESULTS
  LY294002 suppressed cell proliferation but induced apoptosis with decreased levels of phosphorylated Akt. HIF-1alpha expression and VEGF secretion were induced under hypoxic conditions and VEGF protein secretion was significantly decreased by treatment with LY294002. In tumor samples, phosphorylated Akt expression was detected in 57% of the tumors, which was correlated with high VEGF expression, angiogenesis, clinicopathological parameters as well as a poor outcome.
  
  
  CONCLUSIONS
  These findings suggest that phosphorylated Akt (Ser473) reflects the grade of malignancy in human gastric adenocarcinomas, not only in terms of tumor growth but also with respect to tumor angiogenesis.
authors.affiliation: Division of Surgical Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Japan.
authors.forename: Iwao
authors.initials: I
authors.lastname: Kobayashi
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokozaki
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D002867:Chromones; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D009025:Morpholines; D042461:Vascular Endothelial Growth Factor A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt