Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis
Abstract
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…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
STAT3 can promote transcription of proangiogenic factors, including vascular endothelial growth factor and IL-6, leading to paracrine and/or autocrine feedback.
“In addition, STAT3 can promote transcription of proangiogenic factors, including vascular endothelial growth factor and IL-6, leading to paracrine and/or autocrine feedback.91–93”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [92]
Inhibition of STAT3 upstream signaling alone is insufficient to overcome activation of compensatory signaling pathways.
“Furthermore, the inhibition of STAT3 upstream signaling alone is insufficient to overcome the activation of compensatory signaling pathways (12, 13).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [12]
Cites
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
Self-citationThe role of STATs in transcriptional control and their impact on cellular function
Bromberg, J., & Darnell, J. E. (2000) · Oncogene · doi:10.1038/sj.onc.1203476 · Cited by 1,201 · see citing works
Self-citationStat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis
Bowman, T., Broome, M. A., Sinibaldi, D., Wharton, W., Pledger, W. J., Sedivy, J. M., Irby, R., Yeatman, T., Courtneidge, S. A., & Jove, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.131568898 · Cited by 488 · see citing works
Self-citationCaldenhoven, E., van Dijk, T. B., Solari, R., Armstrong, J., Raaijmakers, J. A. M., Lammers, J.-W. J., Koenderman, L., & de Groot, R. P. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.13221 · Cited by 373 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“The IL-6–STAT3 pathway is involved in the epithelial–mesenchymal transition (EMT) (131, 132), tumor migration (133), cancer stemness (130, 134, 135) and the induction of hypoxia-inducible factor-1 α (HIF-1 α ) and vascular endothelial growth factor (VEGF), two key players for angiogenesis (136–140).”
BackgroundYeatman, T. J. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1366 · Cited by 1,113 · see citing works
Immune resistance orchestrated by the tumor microenvironment
Gajewski, T. F., Meng, Y., Blank, C., Brown, I., Kacha, A., Kline, J., & Harlin, H. (2006) · Immunological Reviews · doi:10.1111/j.1600-065x.2006.00442.x · Cited by 437 · see citing works
A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis
Kollmann, K., Heller, G., Schneckenleithner, C., Warsch, W., Scheicher, R., Ott, R. G., Schäfer, M., Fajmann, S., Schlederer, M., Schiefer, A.-I., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.07.012 · Cited by 313 · see citing works
Activation of STAT3 is a marker of poor prognosis in human colorectal cancer
Kusaba, T., Nakayama, T., Yamazumi, K., Yakata, Y., Yoshizaki, A., Inoue, K., Nagayasu, T., & Sekine, I. (2006) · Oncology Reports · doi:10.3892/or.15.6.1445 · Cited by 238 · see citing works
Ernst, M. B., Wunderlich, C. M., Hess, S., Paehler, M., Mesaros, A., Koralov, S. B., Kleinridders, A., Husch, A., Münzberg, H., Hampel, B., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5712-08.2009 · Cited by 185 · see citing works
Zhang, X., Yue, P., Fletcher, S., Zhao, W., Gunning, P. T., & Turkson, J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.01.001 · Cited by 179 · see citing works
Self-citationCurrent status of SRC inhibitors in solid tumor malignancies
Puls, L. N., Eadens, M., & Messersmith, W. (2011) · The Oncologist · doi:10.1634/theoncologist.2010-0408 · Cited by 158 · see citing works
Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer
Landen, C. N., Lin, Y. G., Armaiz Pena, G. N., Das, P. D., Arevalo, J. M., Kamat, A. A., Han, L. Y., Jennings, N. B., Spannuth, W. A., Thaker, P. H., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0858 · Cited by 144 · see citing works
Natural Withanolides in the Treatment of Chronic Diseases
White, P. T., Subramanian, C., Motiwala, H. F., & Cohen, M. S. (2016) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-41334-1_14 · Cited by 139 · see citing works
STAT3-YAP/TAZ signaling in endothelial cells promotes tumor angiogenesis
Shen, Y., Wang, X., Liu, Y., Singhal, M., Gürkaşlar, C., Valls, A. F., Lei, Y., Hu, W., Schermann, G., Adler, H., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abj8393 · Cited by 121 · see citing works
Interleukin-6 Induces Both Cell Growth and VEGF Production in Malignant Mesotheliomas
Adachi, Y., Aoki, C., Yoshio‐Hoshino, N., Takayama, K., Curiel, D. T., & Nishimoto, N. (2006) · International Journal of Cancer · doi:10.1002/ijc.22006 · Cited by 115 · see citing works
Vinores, S. A., Xiao, W., Aslam, S., Shen, J., Oshima, Y., Nambu, H., Liu, H., Carmeliet, P., & Campochiaro, P. A. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20525 · Cited by 99 · see citing works
Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature
Hooglugt, A., van der Stoel, M. M., Boon, R. A., & Huveneers, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.612802 · Cited by 82 · see citing works
Parseghian, C. M., Parikh, N. U., Wu, J. Y., Jiang, Z.-Q., Henderson, L., Tian, F., Pastor, B., Ychou, M., Raghav, K., Dasari, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3138 · Cited by 67 · see citing works
Jin, J., Wu, Y., Zhao, Z., Wu, Y., Zhou, Y.-D., Liu, S., Sun, Q., Yang, G., Lin, J., Nagle, D. G., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.160606 · Cited by 57 · see citing works
“Furthermore, the inhibition of STAT3 upstream signaling alone is insufficient to overcome the activation of compensatory signaling pathways (12, 13).”
Cascio, S., Ferla, R., D'Andrea, A., Gerbino, A., Bazan, V., Surmacz, E., & Russo, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21843 · Cited by 53 · see citing works
Critical analysis of the potential for targeting STAT3 in human malignancy
Grandis, J., & Peyser (2013) · OncoTargets and Therapy · doi:10.2147/ott.s47903 · Cited by 24 · see citing works
Gérard, C., Gonze, D., Lemaigre, F., & Novák, B. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003455 · Cited by 20 · see citing works
- Authors
- Niu, G., Wright, K. L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang, S., Wang, T., Sinibaldi, D., Coppola, D., Heller, R., Ellis, L. M., Karras, J., Bromberg, J., Pardoll, D., Jove, R., & Yu, H.
- Affiliations
- University of South Florida (US)
- Johns Hopkins University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Ionis Pharmaceuticals (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Jove, Richard
- Yu, Hua
- ORCID
- Venue
- Oncogene
- Published
- 2002-03-21
- Volume
- 21
- Issue
- 13
- Pages
- 2000-2008
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2007897471
- Cited by
- 1,207
- References
- 4
- Citations by year
- 2026: 25 · 2025: 20 · 2024: 33 · 2023: 40 · 2022: 50 · 2021: 50 · 2020: 59 · 2019: 34 · 2018: 51 · 2017: 60 · 2016: 64 · 2015: 72 · 2014: 68 · 2013: 63 · 2012: 73
- FWCI
- 12.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA75243, R01CA055652, CA 82533, CA89693, CA-55652, R01CA089693, P01CA082533, R29CA075243)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- STAT3, vascular endothelial growth factor, VEGF expression, tumor angiogenesis, v-Src, tyrosine kinase signaling, VEGF promoter, STAT3 binding sites, dominant-negative STAT3, antisense oligonucleotides, transcriptional regulation, angiogenesis inhibition
- MeSH terms
- Animals, Base Sequence, Cell Line, Transformed, Collagen, DNA-Binding Proteins, Drug Combinations, Humans, Laminin, Lymphokines, Neoplasm Transplantation, Neovascularization, Pathologic, Promoter Regions, Genetic, Proteoglycans, Transfection, Tumor Cells, Cultured, Trans-Activators, Down-Regulation, Oncogene Protein pp60(v-src), Up-Regulation, Gene Expression Regulation, Neoplastic, Endothelial Growth Factors, Mutagenesis, Site-Directed, 3T3 Cells, Electrophoretic Mobility Shift Assay, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, STAT3 Transcription Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
