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  • Original Paper
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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. 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.

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References

  • Akiri G, Nahari D, Finkelstein Y, Le S, Elroy-Stein O and Levi B . (1998). Oncogene, 12, 227–236.

  • Bergers G, Javaherian K, Lo KM, Folkman J and Hanahan D . (1999). Science, 284, 808–812.

  • Bromberg IF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C and Darnell Jr JE . (1999). Cel1, 98, 295–303.

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR and Dvorak HF . Cancer Res., (1993). 53, 4727–4735.

  • Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Femandez-Luna JL, Nunez G, Dalton WS and Jove R . (1999). Immunity, 10, 105–115.

  • Christofori G, Naik P and Hanahan D . (1995). Mol. Endocrinol., 9, 1760–1770.

  • Claffey KP, Shih SC, Mullen A, Dziennis S, Cusick JL, Abrams KR, Lee SW and Detmar M . (1998). Mol. Biol. Cell, 9, 469–481.

  • Clarke K, Smith K, Gullick WJ and Harris AL . (2001). Br. J. Cancer, 84, 1322–1329.

  • Cohen T, Nahari D, Cerem LW, Neufeld G and Levi BZ . (1996). J Biol Chem., 271, 736–741.

  • Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W and Plate KH . (1997). Cancer Res., 57, 3860–3864.

  • Danial NN, Pernis A and Rothman PB . (1995). Science, 269, 1875–1877.

  • Darnell Jr JE . (1997). Science, 277, 1630–1635.

  • Deroanne CF, Hajitou A, Calberg-Bacq CM, Nusgens BV and Lapiere CM . (1997). Cancer Res., 57, 5590–5597.

  • Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y and Fujiikuriyama Y . (1997). Proc. Natl. Acad. Sci. USA, 94, 4273–4278.

  • Evans DB, Abbruzzese JL and Rich TR (1997). Cancer Principles and Practice of Oncology, 5th edn. DeVita VT, Hellman S Rosenberg SA (eds). Lippincot-Raven: New York. pp 1054–1087.

  • Finkenzeller G, Sparacio A, Technau A, Marme D and Siemeister G . Oncogene, (1997). 15, 669–676.

  • Flamme I, Frohlich T, Vonreutern M, Kappel A, Damert A and Risau W . (1997). Mech. Dev., 63, 51–60.

  • Folkman J . (1997). EXS, 79, 1–8.

  • Frank S, Hubner G, Breier G, Longaker MT, Greenhalgh DG and Werner S . (1995). J. Biol. Chem., 270, 12607–12613.

  • Funamoto M, Fujio Y, Negoro S, Tone E, Osugi T, Hirota H, Izumi M, Yoshizaki K, Walsh K, Kishimoto T and Yamauchi-Takihara K . (2000). J. Biol. Chem., 275, 10561–10566.

  • Goad DL, Rubin J, Wang H, Tashjian AH and Patterson C . (1996). Endocrinology, 137, 2262–2268.

  • Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse JF, Capiod JC, Delobel J, Weber-Nordt R, Dusanter-Fourt I, Dreyfus F, Groner B and Prin L . (1996). Blood, 87, 1692–7169.

  • Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS and Tweardy DJ . (1998). J. Clin. Investig., 102, 1385–1392.

  • Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y and Kim JD . (2000). Proc. Natl. Acad. Sci. USA, 97, 4227–4232.

  • Grugel S, Finkenzelle G, Weindel K, Barleon B and Marme D . (1995). J. Biol. Chem., 270, 25915–25919.

  • Hishinuma S, Funamoto M, Fujio Y, Kunisada K and Yamauchi-Takihara K . (1999). Biochem. Biophys. Res. Commun., 264, 436–440.

  • Iliopoulos O, Levy AP, Jiang C, Kaelin Jr WG and Goldberg MA . (1996). Proc. Natl. Acad. Sci. USA, 93, 10595–10599.

  • Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW and Korc M . (1997). Clin. Cancer Res., 3, 1309–1316.

  • Jiang BH, Agani F, Passaniti A and Semenza GL . (1997). Cancer Res., 57, 5328–5335.

  • Kamohara H, Sakamoto K, Ishiko T, Mita S, Masuda Y, Abe T and Ogawa M . (1994). Res. Commun. Mol. Pathol. Pharmacol., 85, 131–140.

  • Kern SE . (2000). Med. Clin. North Am., 84, 691–695.

  • Kieser A, Welch HA, Brandner G, Marme D and Kolch W . (1994). Oncogene 9, 963–969.

  • Korc M . (1998). Surg. Oncol. Clin. N. Am., 7, 25–41.

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV and Ferrara N . (1989). Science, 246, 1306–1309.

  • Levy AP, Levy NS, Wegner S and Goldberg MA . (1995). J. Biol. Chem., 270, 13333–13340.

  • Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F and Lee ME . (1995). J. Biol. Chem., 270, 308–312.

  • Liu YX, Cox SR, Morita T and Kourembanas S . (1995). Circ. Res., 77, 638–643.

  • Morgan RT, Woods LK, Moore GE, Quinn LA, McGavran L and Gordon SG . (1980). Int. J. Cancer, 25, 591–598.

  • Ni Z, Lou W, Leman ES and Gao AC . (2000). Cancer Res., 60, 1225–1228.

  • Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R and Yu H . (2002). Oncogene, 21, 2000–2008.

  • Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O Alitalo K . (1994). J. Biol. Chem., 269, 6271–6274.

  • Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T and Kerbel RS . (1995). Cance Res., 55, 4575–4580.

  • Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K and Kuwano M . (1996). J. Biol. Chem., 271, 28220–28228.

  • Schindler C and Damel Jr JE (1995). Annu. Rev. Biochem., 64, 621–651.

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS and Dvorak HF . (1983). Science, 219, 983–985.

  • Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q and Xie K . (1999). Clin. Cancer Res., 5, 7234–7243.

  • Shi Q, Le X, Peng Z, Tang H, Xiong Q, Wang B, Li X-C, Abbruzzes JL and Xie K . (2001a). Cancer Res., 61, 4143–4154.

  • Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y and Xie K . (2001b). Oncogene, 20, 3751–3756.

  • Shweiki D, Itin A, Soffer D and Keshet E . (1992). Nature (London), 359, 843–845.

  • Stein I, Itin A, Einat P, Skaliter R, Grossman Z and Keshet E . (1998). Mol. Biol. Cell, 18, 3112–3119.

  • Stein I, Neeman M, Shweiki D, Itin A and Keshet E . (1995). Mol. Cell Biol., 15, 5363–5368.

  • Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC and Abraham JA . (1991). J. Biol. Chem., 266, 11947–11954.

  • Vanmeir EG, Polverini PJ, Chazin VR, Huang HJS, Detribolet N and Cavenee WK . (1994). Nat. Genet., 8, 171–176.

  • Vezeridis MP, Meitner PA, Tibbetts LM, Doremus CM, Tzanakakis G and Calabresi P . (1990). J. Surg. Res., 48, 51–55.

  • Wang B, Shi Q, Abbruzzeze JL, Xiong Q, Le X, and Xie K . (2001). Intl. J. Pancreatol., 29, 37–46.

  • Wang D, Huang HJ, Kazlauskas A and Cavenee WK . (1999). Cancer Res., 59, 1464–1472.

  • Watson CJ and Mille WR . (1995). Br. J. Cancer, 71, 840–844.

  • Yu CL, Meyer DJ, Campbell GS, Lamer AC, Carter-Su C, Schwartz J and Jove R . (1995). Science, 269, 81–83.

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Acknowledgements

This work was supported in part by the Topfer Foundation for Pancreatic Cancer Research, the Research Project Grant #RPG-00-054-01-CMS from the American Cancer Society, the WM Keck Foundation for Cancer Gene Therapy, the Physician Referral Service Award, and Cancer Center Support Core Grant CA 16672-23 from the National Cancer Institute, National Institutes of Health. We thank Judy King for expert help in the preparation of this manuscript and Don Norwood for editorial comments.

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Correspondence to Keping Xie.

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Wei, D., Le, X., Zheng, L. et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319–329 (2003). https://doi.org/10.1038/sj.onc.1206122

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