PMID- 17984117
OWN - NLM
STAT- MEDLINE
DCOM- 20080331
LR  - 20091119
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 29
IP  - 1
DP  - 2008 Jan
TI  - A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT 
      contributes to angiogenesis in human gastric cancer.
PG  - 44-51
AB  - 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.
FAU - Lee, Byung Lan
AU  - Lee BL
AD  - Department of Anatomy, Seoul National University College of Medicine, Seoul 
      110-799, Korea.
FAU - Kim, Woo Ho
AU  - Kim WH
FAU - Jung, Jieun
AU  - Jung J
FAU - Cho, Sung Jin
AU  - Cho SJ
FAU - Park, Jong-Wan
AU  - Park JW
FAU - Kim, Jihyen
AU  - Kim J
FAU - Chung, Hee-Yong
AU  - Chung HY
FAU - Chang, Mee Soo
AU  - Chang MS
FAU - Nam, Seon Young
AU  - Nam SY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071104
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (DNA Primers)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - DNA Primers
MH  - Enzyme Activation
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Nude
MH  - *Neovascularization, Pathologic
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Messenger/genetics
MH  - Stomach Neoplasms/*blood supply/enzymology/metabolism
MH  - *Up-Regulation
MH  - Vascular Endothelial Growth Factor A/genetics
EDAT- 2007/11/07 09:00
MHDA- 2008/04/01 09:00
CRDT- 2007/11/07 09:00
PHST- 2007/11/07 09:00 [pubmed]
PHST- 2008/04/01 09:00 [medline]
PHST- 2007/11/07 09:00 [entrez]
AID - bgm232 [pii]
AID - 10.1093/carcin/bgm232 [doi]
PST - ppublish
SO  - Carcinogenesis. 2008 Jan;29(1):44-51. doi: 10.1093/carcin/bgm232. Epub 2007 Nov 
      4.