Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.
Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (Stat3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with Stat3 activity in diverse human cancer cell lines. An activated Stat3 mutant (Stat3C) up-regulates VEGF expression and stimulates tumor angiogenesis. Stat3C-induced VEGF up-regulation is abrogated when a Stat3-binding site in the VEGF promoter is mutated. Furthermore, interrupting Stat3 signaling with dominant-negative Stat3 protein or Stat3 antisense oligonucleotide in tumor cells down-regulates VEGF expression. Consistent with an important role of Stat3 in VEGF up-regulation induced by various oncogenic tyrosine kinases, v-Src-mediated VEGF expression is inhibited when Stat3 signaling is blocked. Moreover, chromatin immunoprecipitation assays indicate that Stat3 protein binds to the VEGF promoter in vivo and mutation of a Stat3-binding site in the VEGF promoter abrogates v-Src-induced VEGF promoter activity. These studies provide evidence that the VEGF gene is regulated directly by Stat3 protein, and indicate that Stat3 represents a common molecular target for blocking angiogenesis induced by multiple signaling pathways in human cancers.
Niu
Guilian
G
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida College of Medicine, Tampa, Florida, FL 33612, USA.
Wright
Kenneth L
KL
Huang
Mei
M
Song
Lanxi
L
Haura
Eric
E
Turkson
James
J
Zhang
Shumin
S
Wang
Tianhong
T
Sinibaldi
Dominic
D
Coppola
Domenico
D
Heller
Richard
R
Ellis
Lee M
LM
Karras
James
J
Bromberg
Jacqueline
J
Pardoll
Drew
D
Jove
Richard
R
Yu
Hua
H
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D003094:Collagen; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004338:Drug Combinations; D024202:Electrophoretic Mobility Shift Assay; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen; D015688:Oncogene Protein pp60(v-src)