S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells
- Jung, Joo Eun; Lee, Hyun-Gyu; Cho, Ik-Hyun; Chung, Doo Hyun; Yoon, Sun-Hee; Yang, Young Mok; Lee, Jung Weon; Choi, Seongwon; Park, Jong-Wan; Ye, Sang-Kyu; Chung, Myung-Hee
- Issue Date
- FASEB J. 2005 Aug;19(10):1296-8. Epub 2005 May 26.
- Animals; COS Cells; Cell Hypoxia; Cell Line, Tumor; Cercopithecus aethiops; *Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/*physiology; Ischemia/metabolism; Kidney/blood supply/metabolism; Kidney Neoplasms/*metabolism; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor/*physiology; Transcription, Genetic; Vascular Endothelial Growth Factor A/*genetics; p300-CBP Transcription Factors/physiology
- 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.
- 1530-6860 (Electronic)
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