title: STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells.
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.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.forename: Ik Hyun
authors.initials: IH
authors.lastname: Cho
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.forename: Seongwon
authors.initials: S
authors.lastname: Choi
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Chung
mesh_terms: D000818:Animals; D019556:COS Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors