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 fact...
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| Veröffentlicht in: | Nucleic acids research 2016-10, Vol.44 (18), p.8693-8703 |
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| creator | Liu, Ning Ding, Deqiang Hao, Wanyu Yang, Fan Wu, Xiaoying Wang, Miao Xu, Xiaoling Ju, Zhenyu Liu, Jun-Ping Song, Zhangfa Shay, Jerry W Guo, Yunliang Cong, Yu-Sheng |
| description | 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. |
| doi_str_mv | 10.1093/nar/gkw549 |
| format | Article |
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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.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkw549</identifier><identifier>PMID: 27325744</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Carcinogenesis - metabolism ; Carcinogenesis - pathology ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Gene regulation, Chromatin and Epigenetics ; HeLa Cells ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Mice, Inbred C57BL ; Neovascularization, Pathologic - metabolism ; Neovascularization, Physiologic ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; Promoter Regions, Genetic ; Protein Binding - genetics ; Sp1 Transcription Factor - metabolism ; Stomach Neoplasms - blood supply ; Stomach Neoplasms - genetics ; Telomerase - metabolism ; Transcription, Genetic ; Up-Regulation - genetics ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Nucleic acids research, 2016-10, Vol.44 (18), p.8693-8703</ispartof><rights>The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-8c06799f4d8966d09c6fce5a757de736feae129e4a09241082aa8effd9ff6d9c3</citedby><cites>FETCH-LOGICAL-c378t-8c06799f4d8966d09c6fce5a757de736feae129e4a09241082aa8effd9ff6d9c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062966/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062966/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27325744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Ning</creatorcontrib><creatorcontrib>Ding, Deqiang</creatorcontrib><creatorcontrib>Hao, Wanyu</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Wu, Xiaoying</creatorcontrib><creatorcontrib>Wang, Miao</creatorcontrib><creatorcontrib>Xu, Xiaoling</creatorcontrib><creatorcontrib>Ju, Zhenyu</creatorcontrib><creatorcontrib>Liu, Jun-Ping</creatorcontrib><creatorcontrib>Song, Zhangfa</creatorcontrib><creatorcontrib>Shay, Jerry W</creatorcontrib><creatorcontrib>Guo, Yunliang</creatorcontrib><creatorcontrib>Cong, Yu-Sheng</creatorcontrib><title>hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>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.</description><subject>Animals</subject><subject>Carcinogenesis - metabolism</subject><subject>Carcinogenesis - pathology</subject><subject>Cell Proliferation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation, Chromatin and Epigenetics</subject><subject>HeLa Cells</subject><subject>Human Umbilical Vein Endothelial Cells - metabolism</subject><subject>Humans</subject><subject>Mice, Inbred C57BL</subject><subject>Neovascularization, Pathologic - metabolism</subject><subject>Neovascularization, Physiologic</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Binding - genetics</subject><subject>Sp1 Transcription Factor - metabolism</subject><subject>Stomach Neoplasms - blood supply</subject><subject>Stomach Neoplasms - genetics</subject><subject>Telomerase - metabolism</subject><subject>Transcription, Genetic</subject><subject>Up-Regulation - genetics</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1LwzAYx4Mobk4vfgDJWahL2jRtLoLINoWBoNNryNKkja5JSbKNfXs7pkNPz-H_9vAD4BqjO4xYNrbCj-uvbU7YCRjijKYJYTQ9BUOUoTzBiJQDcBHCJ0KY4Jycg0FaZGleEDIEdbOYvC5g513rogowrlvnobC1cbWyKpgAlzsoZDQbEY2t4cdkNoUbI6CxUfm94GyAWxMbGBsF3zoMoxc2SG-6vQZ173H-EpxpsQrq6ueOwPt0snh8SuYvs-fHh3kis6KMSSkRLRjTpCoZpRVikmqpclHkRaWKjGolFE6ZIgKxlGBUpkKUSuuKaU0rJrMRuD_0dutlqyqpbP_NinfetMLvuBOG_1esaXjtNjxHNO0n-4LbQ4H0LgSv9DGLEd_j5j1ufsDdm2_-rh2tv3yzb7-3gDM</recordid><startdate>20161014</startdate><enddate>20161014</enddate><creator>Liu, Ning</creator><creator>Ding, Deqiang</creator><creator>Hao, Wanyu</creator><creator>Yang, Fan</creator><creator>Wu, Xiaoying</creator><creator>Wang, Miao</creator><creator>Xu, Xiaoling</creator><creator>Ju, Zhenyu</creator><creator>Liu, Jun-Ping</creator><creator>Song, Zhangfa</creator><creator>Shay, Jerry W</creator><creator>Guo, Yunliang</creator><creator>Cong, Yu-Sheng</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20161014</creationdate><title>hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor</title><author>Liu, Ning ; Ding, Deqiang ; Hao, Wanyu ; Yang, Fan ; Wu, Xiaoying ; Wang, Miao ; Xu, Xiaoling ; Ju, Zhenyu ; Liu, Jun-Ping ; Song, Zhangfa ; Shay, Jerry W ; Guo, Yunliang ; Cong, Yu-Sheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-8c06799f4d8966d09c6fce5a757de736feae129e4a09241082aa8effd9ff6d9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Carcinogenesis - metabolism</topic><topic>Carcinogenesis - pathology</topic><topic>Cell Proliferation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene regulation, Chromatin and Epigenetics</topic><topic>HeLa Cells</topic><topic>Human Umbilical Vein Endothelial Cells - metabolism</topic><topic>Humans</topic><topic>Mice, Inbred C57BL</topic><topic>Neovascularization, Pathologic - metabolism</topic><topic>Neovascularization, Physiologic</topic><topic>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Binding - genetics</topic><topic>Sp1 Transcription Factor - metabolism</topic><topic>Stomach Neoplasms - blood supply</topic><topic>Stomach Neoplasms - genetics</topic><topic>Telomerase - metabolism</topic><topic>Transcription, Genetic</topic><topic>Up-Regulation - genetics</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Ning</creatorcontrib><creatorcontrib>Ding, Deqiang</creatorcontrib><creatorcontrib>Hao, Wanyu</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Wu, Xiaoying</creatorcontrib><creatorcontrib>Wang, Miao</creatorcontrib><creatorcontrib>Xu, Xiaoling</creatorcontrib><creatorcontrib>Ju, Zhenyu</creatorcontrib><creatorcontrib>Liu, Jun-Ping</creatorcontrib><creatorcontrib>Song, Zhangfa</creatorcontrib><creatorcontrib>Shay, Jerry W</creatorcontrib><creatorcontrib>Guo, Yunliang</creatorcontrib><creatorcontrib>Cong, Yu-Sheng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Ning</au><au>Ding, Deqiang</au><au>Hao, Wanyu</au><au>Yang, Fan</au><au>Wu, Xiaoying</au><au>Wang, Miao</au><au>Xu, Xiaoling</au><au>Ju, Zhenyu</au><au>Liu, Jun-Ping</au><au>Song, Zhangfa</au><au>Shay, Jerry W</au><au>Guo, Yunliang</au><au>Cong, Yu-Sheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2016-10-14</date><risdate>2016</risdate><volume>44</volume><issue>18</issue><spage>8693</spage><epage>8703</epage><pages>8693-8703</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>27325744</pmid><doi>10.1093/nar/gkw549</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carcinogenesis - metabolism Carcinogenesis - pathology Cell Proliferation Gene Expression Regulation, Neoplastic Gene regulation, Chromatin and Epigenetics HeLa Cells Human Umbilical Vein Endothelial Cells - metabolism Humans Mice, Inbred C57BL Neovascularization, Pathologic - metabolism Neovascularization, Physiologic Platelet Endothelial Cell Adhesion Molecule-1 - metabolism Promoter Regions, Genetic Protein Binding - genetics Sp1 Transcription Factor - metabolism Stomach Neoplasms - blood supply Stomach Neoplasms - genetics Telomerase - metabolism Transcription, Genetic Up-Regulation - genetics Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
| title | hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor |
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