Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis
Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Sta...
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| Veröffentlicht in: | Oncogene 2003-01, Vol.22 (3), p.319-329 |
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| creator | Wei, Daoyan Le, Xiangdong Zheng, Leizhen Wang, Liwei Frey, Jennifer A Gao, Allen C Peng, Zhihai Huang, Suyun Xiong, Henry Q Abbruzzese, James L Xie, Keping |
| description | Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis
in vivo
. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer. |
| doi_str_mv | 10.1038/sj.onc.1206122 |
| format | Article |
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in vivo
. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1206122</identifier><identifier>PMID: 12545153</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Animals ; Apoptosis ; Biological and medical sciences ; Carcinogenicity Tests ; Cell Biology ; Cell Nucleus - metabolism ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Down-Regulation ; Endothelial Growth Factors - genetics ; Endothelial Growth Factors - metabolism ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation ; Genes, Dominant ; Human Genetics ; Humans ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Internal Medicine ; Liver Neoplasms - secondary ; Lymphokines - genetics ; Lymphokines - metabolism ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Molecular and cellular biology ; Neovascularization, Pathologic ; Oncology ; original-paper ; Pancreas - blood supply ; Pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Promoter Regions, Genetic ; Signal Transduction ; STAT3 Transcription Factor ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Tumor Cells, Cultured ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors</subject><ispartof>Oncogene, 2003-01, Vol.22 (3), p.319-329</ispartof><rights>Springer Nature Limited 2003</rights><rights>2003 INIST-CNRS</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 23, 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c564t-8d9a0216426a5e28b485d5eaecc8f6c5e5824b8d905d115a6473b1b00e9ef86f3</citedby><cites>FETCH-LOGICAL-c564t-8d9a0216426a5e28b485d5eaecc8f6c5e5824b8d905d115a6473b1b00e9ef86f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1206122$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1206122$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14680621$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12545153$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Daoyan</creatorcontrib><creatorcontrib>Le, Xiangdong</creatorcontrib><creatorcontrib>Zheng, Leizhen</creatorcontrib><creatorcontrib>Wang, Liwei</creatorcontrib><creatorcontrib>Frey, Jennifer A</creatorcontrib><creatorcontrib>Gao, Allen C</creatorcontrib><creatorcontrib>Peng, Zhihai</creatorcontrib><creatorcontrib>Huang, Suyun</creatorcontrib><creatorcontrib>Xiong, Henry Q</creatorcontrib><creatorcontrib>Abbruzzese, James L</creatorcontrib><creatorcontrib>Xie, Keping</creatorcontrib><title>Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis
in vivo
. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.</description><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - pathology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Carcinogenicity Tests</subject><subject>Cell Biology</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. 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However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis
in vivo
. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein–DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12545153</pmid><doi>10.1038/sj.onc.1206122</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; SpringerLink Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adenocarcinoma - genetics Adenocarcinoma - metabolism Adenocarcinoma - pathology Animals Apoptosis Biological and medical sciences Carcinogenicity Tests Cell Biology Cell Nucleus - metabolism Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Down-Regulation Endothelial Growth Factors - genetics Endothelial Growth Factors - metabolism Female Fundamental and applied biological sciences. Psychology Gene Expression Regulation Genes, Dominant Human Genetics Humans Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Internal Medicine Liver Neoplasms - secondary Lymphokines - genetics Lymphokines - metabolism Medicine Medicine & Public Health Mice Mice, Inbred BALB C Molecular and cellular biology Neovascularization, Pathologic Oncology original-paper Pancreas - blood supply Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Promoter Regions, Genetic Signal Transduction STAT3 Transcription Factor Trans-Activators - genetics Trans-Activators - metabolism Tumor Cells, Cultured Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors |
| title | Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis |
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