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 by multiple signaling pathways in human cancers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- Stat3:
-
signal transducer and activation of transcription 3
- VEGF:
-
vascular endothelial growth factor
- IL-6:
-
interleukin-6
- EGF:
-
epithelial growth factor
- EMSA:
-
electrophoretic mobility shift assay
References
Akagi Y, Liu W, Zebrowski B, Xie K, Ellis LM . 1998 Cancer Res. 58: 4008–4014
Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R . 2001 Proc. Natl. Acad. Sci. USA 98: 7319–7324
Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2488
Bromberg J, Darnell Jr JE . 2000 Oncogene 19: 2468–2473
Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell Jr JE . 1998 Mol. Cell. Biol. 18: 2553–2558
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE . 1999 Cell 98: 295–303
Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JAM, Lammers JWJ, Koenderman L, de Groot RP . 1996 J. Biol. Chem. 271: 13221–13227
Catlett-Falcone R, Dalton WS, Jove R . 1999a Curr. Opin. Oncol. 11: 490–496
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . 1999b Immunity 10: 105–115
Coughlin CM, Salhany KE, Gee MS, LaTemple DC, Kotenko S, Ma X, Gri G, Wysocka M, Kim JE, Liu L, Liao F, Farber JM, Pestka S, Trinchieri G, Lee WM . 1998 Immunity 9: 25–34
Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM, Serve H, Berdel WE, Kienast J . 2000 Blood 95: 2630–2636
Deng WP, Nickoloff JA . 1992 Anal. Biochem. 200: 81–88
Dong Z, Greene G, Pettaway C, Dinney CP, Eue I, Lu W, Bucana CD, Balbay MD, Bielenberg D, Fidler IJ . 1999 Cancer Res. 59: 872–879
Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, Gallick GE . 1998 J. Biol. Chem. 273: 1052–1057
Folkman J . 1995 N. Engl. J. Med. 333: 1757–1763
Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, Hirota H, Izumi M, Yoshizaki K, Walsh K, Kishimoto T, Yamauchi-Takihara K . 2000 J. Biol. Chem. 275: 10561–10566
Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox C, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R . 2001 Oncogene 20: 2499–2513
Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R . 1997 Cell. Growth Differ. 8: 1267–1276
Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, Tweardy DJ . 1998 J. Clin. Invest. 102: 1385–1392
Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD . 2000 Proc. Natl. Acad. Sci. USA 97: 4227–4232
Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS . 1999 Cancer Res. 59: 1592–1598
Jiang BH, Zheng JZ, Aoki M, Vogt PK . 2000 Proc. Natl. Acad. Sci. USA 97: 1749–1753
Khazaie K, Schirrmacher V, Lichtner RB . 1993 Cancer Metastasis Rev. 12: 255–274
Luttrell DK, Lee A, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez M, Berman J, Gilmer TM . 1994 Proc. Natl. Acad. Sci. USA 91: 83–87
Luttrell DK, Luttrell LM, Parsons SJ . 1988 Mol. Cell Biol. 9: 497–501
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A . 1994 Nature 367: 576–579
Mukhopadhyay D, Tsiokas L, Sukhatme VP . 1995a Cancer Res. 55: 6161–6165
Mukhopadhyay D, Tsiokas L, Zhou X-M, Foster D, Brugge JS, Sukhatme VP . 1995b Nature 375: 577–581
Muthuswamy SK, Muller WJ . 1995 Oncogene 11: 271–279
Ni Z, Lou W, Leman ES, Gao AC . 2000 Cancer Res. 60: 1225–1228
Niu G, Heller R, Catlett-Falcone R, Coppola D, Jaroszeski M, Dalton W, Jove R, Yu H . 1999 Cancer Res. 59: 5059–5063
Pages G, Milanini J, Richard DE, Berra E, Gothie E, Vinals F, Pouyssegur J . 2000 Ann. N. Y. Acad. Sci. 902: 187–200
Passaniti A, Taylor RM, Pili R, Guo R, Long PV, Haney JA, Grant DS, Martin GR . 1992 Lab. Invest. 67: 519–528
Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS . 1997 Am. J. Pathol. 151: 1523–1530
Plate KH, Breier G, Weich HA, Risau W . 1992 Nature 359: 845–848
Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS . 1995 Cancer Res. 55: 4575–4580
Rak J, Yu JL, Klement G, Kerbel RS . 2000 J. Investig. Dermatol. Symp. Proc. 5: 24–33
Seidel HM, Milocco LH, Lamb P, Darnell Jr JE, Stein RB, Rosen J . 1995 Proc. Natl. Acad. Sci. USA 92: 3041–3045
Shweiki D, Itin A, Soffer D, Keshet E . 1992 Nature 359: 843–845
Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger WJ, Jove R . 2000 Oncogene 19: 5419–5427
Turkson J, Bowman T, Garcia R, Caldenhoven E, de Groot RP, Jove R . 1998 Mol. Cell Biol. 18: 2545–2552
Turkson J, Jove R . 2000 Oncogene 19: 6613–6626
Volpert OV, Dameron KM, Bouck N . 1997 Oncogene 14: 1495–1502
Wagner BJ, Hayes TE, Hoban CJ, Cochran BH . 1990 EMBO J. 9: 4477–4484
Wells J, Boyd KE, Fry CJ, Bartley SM, Farnham PJ . 2000 Mol. Cell Biol. 20: 5797–5807
Wiener JR, Nakano K, Kruzelock RP, Bucana CD, Bast Jr RC, Gallick GE . 1999 Clin. Cancer Res. 5: 2164–2170
Xu X, Sun YL, Hoey T . 1996 Science 273: 794–797
Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R . 1995 Science 269: 81–83
Zhang D, Sun M, Samols D, Kushner I . 1996 J. Biol. Chem. 271: 9503–9509
Acknowledgements
This work was supported by National Institutes of Health (CA75243, CA89693, CA55652 and CA82533) and by the Dr Tsai-Fan Yu Cancer Research Endowment. We would like to thank Anita Larson for assisting with preparation of the manuscript, Dr Judith Abraham for providing the VEGF promoter and Wenbiao Liu for technical support. This work has been supported in part by the Molecular Biology Core Facility and Biostatistics Core Facility at the H Lee Moffitt Cancer Center and Research Institute.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Niu, G., Wright, K., Huang, M. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002). https://doi.org/10.1038/sj.onc.1205260
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205260
Keywords
This article is cited by
-
Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery
Journal of Experimental & Clinical Cancer Research (2024)
-
A robust optimal control framework for controlling aberrant RTK signaling pathways in esophageal cancer
Journal of Mathematical Biology (2024)
-
Molecular targets and therapeutic strategies for triple-negative breast cancer
Molecular Biology Reports (2023)
-
Vascular endothelial growth factor antagonist peptides inhibit tumor growth and metastasis in breast cancer through repression of c-src and STAT3 genes
Molecular Biology Reports (2023)
-
TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness
Cellular and Molecular Life Sciences (2023)