hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor.
Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the VEGF promoter and the transcription factor Sp1. hTERT binds to Sp1 in vitro and in vivo and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the mTert gene in the first generation of Tert null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the VEGF gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance.
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Ning
N
Liu
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Deqiang
D
Ding
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Wanyu
W
Hao
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Fan
F
Yang
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Xiaoying
X
Wu
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Miao
M
Wang
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Xiaoling
X
Xu
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Zhenyu
Z
Ju
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
Jun-Ping
JP
Liu
Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou 310016, China.
Zhangfa
Z
Song
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jerry W
JW
Shay
Institute of Cerebrovascular Diseases, Affiliated Hospital of Qingdao University, Qingdao 266003, China.
Yunliang
Y
Guo
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China yscong@hznu.edu.cn.
Yu-Sheng
YS
Cong
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000235:genetics; D019098:Telomerase / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C509186:TERT protein, human; D019098:Telomerase