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STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells

Cited 284 time in Web of Science Cited 300 time in Scopus
Authors
Jung, J. E.; Lee, H. G.; Cho, I. H.; Chung, D. H.; Yoon, S. H.; Yang, Y. M.; Lee, J. W.; Choi, S.; Park, J. W.; Ye, S. K.; Chung, M. H.
Issue Date
2005-05-28
Publisher
Federation of American Society of Experimental Biology (FASEB)
Citation
FASEB J. 2005 Aug;19(10):1296-8. Epub 2005 May 26.
Keywords
AnimalsCOS CellsCell HypoxiaCell Line, TumorCercopithecus aethiops*Gene Expression RegulationHumansHypoxia-Inducible Factor 1, alpha Subunit/*physiologyIschemia/metabolismKidney/blood supply/metabolismKidney Neoplasms/*metabolismPromoter Regions, GeneticRatsRats, Sprague-DawleySTAT3 Transcription Factor/*physiologyTranscription, GeneticTranscription, Geneticp300-CBP Transcription Factors/physiology
Abstract
Aberrantly enhanced vascular endothelial growth factor (VEGF) gene expression is associated with increased tumor growth and metastatic spread of solid malignancies, including human renal carcinomas. Persistent activation of STAT3 is linked to tumor-associated angiogenesis, but underlying mechanisms remain unclear. Therefore, we examined whether STAT3 modulates the stability and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), and in turn enhances VEGF expression. We found that STAT3 was activated in ischemic rat kidneys and hypoxic human renal carcinoma cells. We also found that hypoxia-induced activation of STAT3 transactivated the VEGF promoter and increased the expression of VEGF transcripts. Consistent with these findings, STAT3 inhibition attenuated the hypoxic induction of VEGF. Interestingly, activated STAT3 increased HIF-1alpha protein levels due to the HIF-1alpha stability by blocking HIF-1alpha degradation and accelerated its de novo synthesis. The novel interaction of STAT3 with HIF-1alpha was identified in hypoxic renal carcinoma cells. Furthermore, hypoxia recruited STAT3, HIF-1alpha, and p300 to the VEGF promoter and induced histone H3 acetylation. Therefore, these findings provide compelling evidence that a causal relationship exists between STAT3 activation and HIF-1-dependent angiogenesis and suggest that therapeutic modalities designed to disrupt STAT3 signaling hold considerable promise for the blocking tumor growth and enhancing apoptosis of cancer cells and tissues.
ISSN
1530-6860 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15919761

http://hdl.handle.net/10371/22637
DOI
https://doi.org/10.1096/fj.04-3099fje
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College of Medicine/School of Medicine (의과대학/대학원)Immunology (면역학전공)Journal Papers (저널논문_면역학전공)
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