Journal Article

A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer

Byung Lan Lee, Woo Ho Kim, Jieun Jung, Sung Jin Cho, Jong-Wan Park, Jihyen Kim, Hee-Yong Chung, Mee Soo Chang and Seon Young Nam

in Carcinogenesis

Volume 29, issue 1, pages 44-51
Published in print January 2008 | ISSN: 0143-3334
Published online November 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm232
A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer

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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-1α 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-1α 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-1α in 29% of samples. Moreover, HIF-1α 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-1α 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-1α immunoreactivity than those derived from vector control cells. Thus, we propose that the hypoxia-independent promotion of the AKT–HIF-1α–VEGF pathway contributes, at least in part, to gastric cancer tumorigenesis and angiogenesis.

Journal Article.  4745 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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