Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

Daoyan Wei, Xiangdong Le, Leizhen Zheng, Liwei Wang, Jennifer A. Frey, Allen C Gao, Zhihai Peng, Suyun Huang, Henry Q. Xiong, James L. Abbruzzese, Keping Xie

Research output: Contribution to journalArticle

398 Citations (Scopus)

Abstract

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. Immunohisto-chemical 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 Star3 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.

Original languageEnglish (US)
Pages (from-to)319-329
Number of pages11
JournalOncogene
Volume22
Issue number3
DOIs
StatePublished - Jan 23 2003
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Vascular Endothelial Growth Factor A
Neoplasm Metastasis
Angiogenic Proteins
human VEGFA protein
DNA-Binding Proteins
Growth
Mutagenesis
Cell Line

Keywords

  • Angiogenesis
  • Metastasis
  • Pancreas
  • Stat3
  • Tumor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. / 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.

In: Oncogene, Vol. 22, No. 3, 23.01.2003, p. 319-329.

Research output: Contribution to journalArticle

Wei, D, Le, X, Zheng, L, Wang, L, Frey, JA, Gao, AC, Peng, Z, Huang, S, Xiong, HQ, Abbruzzese, JL & Xie, K 2003, 'Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis', Oncogene, vol. 22, no. 3, pp. 319-329. https://doi.org/10.1038/sj.onc.1206122
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. / Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. In: Oncogene. 2003 ; Vol. 22, No. 3. pp. 319-329.
@article{00b0817d83c24513a8d34e3856af9445,
title = "Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis",
abstract = "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. Immunohisto-chemical 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 Star3 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.",
keywords = "Angiogenesis, Metastasis, Pancreas, Stat3, Tumor",
author = "Daoyan Wei and Xiangdong Le and Leizhen Zheng and Liwei Wang and Frey, {Jennifer A.} and Gao, {Allen C} and Zhihai Peng and Suyun Huang and Xiong, {Henry Q.} and Abbruzzese, {James L.} and Keping Xie",
year = "2003",
month = "1",
day = "23",
doi = "10.1038/sj.onc.1206122",
language = "English (US)",
volume = "22",
pages = "319--329",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

AU - Wei, Daoyan

AU - Le, Xiangdong

AU - Zheng, Leizhen

AU - Wang, Liwei

AU - Frey, Jennifer A.

AU - Gao, Allen C

AU - Peng, Zhihai

AU - Huang, Suyun

AU - Xiong, Henry Q.

AU - Abbruzzese, James L.

AU - Xie, Keping

PY - 2003/1/23

Y1 - 2003/1/23

N2 - 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. Immunohisto-chemical 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 Star3 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.

AB - 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. Immunohisto-chemical 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 Star3 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.

KW - Angiogenesis

KW - Metastasis

KW - Pancreas

KW - Stat3

KW - Tumor

UR - http://www.scopus.com/inward/record.url?scp=0037461934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037461934&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1206122

DO - 10.1038/sj.onc.1206122

M3 - Article

C2 - 12545153

AN - SCOPUS:0037461934

VL - 22

SP - 319

EP - 329

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 3

ER -