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  • Original Paper
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The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

Abstract

Transforming growth factor-beta (TGF-β) signaling is dependent on the heterodimerization of the type II TGF-β receptor (TβRII) with the type I TGF-β receptor (TβRI). Activated TβRI then mediates TGF-β signals by inducing the phosphorylation of Smad2 and/or Smad3, which separately hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of Smad2/Smad3 by activated TβRI is inhibited by two newly discovered members of the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells with a full-length Smad7 construct leads to complete loss of the growth inhibitory response to TGF-β1, without altering TGF-β1-mediated induction of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced anchorage-independent growth and accelerated growth in nude mice. These findings point to a previously unrecognized mechanism for selective suppression of TGF-β-mediated growth inhibition in cancer cells that allows for continued activation of the PAI-I promoter by TGF-β1, which may act to enhance the tumorigenicity of certain cancer cells.

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References

  • Afrakhte M, Moren A, Jossan S, Itoh S, Sampath K, Westermark B, Heldin CH, Heldin NE and ten Dijke P. . 1998 Biochem. Biophys. Res. Commu. 249: 505–511.

  • Baldwin RL, Friess H, Yokoyama M, Lopez ME, Kobrin MS, Büchler MW and Korc M. . 1996 Int. J. Cancer 67: 283–288.

  • Baldwin RL and Korc M. . 1993 Growth Factors 8: 23–34.

  • Bergmann U, Funatomi H, Yokoyama M, Beger HG and Korc M. . 1995 Cancer Res. 55: 2007–2011.

  • Carcamo J, Weis FM, Ventura F, Wieser R, Wrana JL, Attisano L and Massagué J. . 1994 Mol. Cell. Biol. 14: 3810–3821.

  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y and Wang XF. . 1995 Proc. Natl. Acad. Sci. USA 92: 5545–5449.

  • DeCoteau JF, Knaus PI, Yankelev-Reis H, Lowsky R, Lodish HF and Kadin ME. . 1997 Proc. Natl. Acad. Sci. USA 94: 5877–81.

  • Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL and Attisano L. . 1996 Cell 86: 543–552.

  • Freeman JW, Mattingly CA and Strodel WE. . 1995 J. Cell Physiol. 165: 155–163.

  • Friess H, Yamanaka Y, Büchler M, Berger HG, Kobrin MS, Baldwin RL and Korc M. . 1993a Cancer Res. 53: 2704–2707.

  • Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG, Gold LI and Korc M. . 1993b Gastroenterology 105: 1846–1856.

  • Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N and Berger HG. . 1997 Cancer Res. 57: 1634–1637.

  • Goggins M, Shekker M, Turnacioglu K, Yeo CJ, Hruban RH and Kern SE. . 1998 Cancer Res. 58: 5329–5332.

  • Grau AM, Zhang L, Wang W, Evans DB, Abbruzzese JL, Zhang W and Chiao PJ. . 1997 Cancer Res. 57: 3929–3934.

  • Grondahl Hansen J, Hilsenbeck SG, Christensen IJ, Clark GM, Osborne CK and Brünner N. . 1997 Breast Cancer Res. Treat. 43: 153–163.

  • Hahn SA, Schutte M, Hoque AT, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE. . 1996 Science 271: 350–353.

  • Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone Jr MA, Wrana JL and Falb D. . 1997 Cell 89: 1165–1173.

  • Heldin CH, Miyazono K and tenDijke K. . 1997 Nature 390: 465–471.

  • Hofmann R, Lehmer A, Buresch M, Hartung R and Ulm K. . 1996 Cancer 78: 487–492.

  • Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M and Miyazono K. . 1997 Nature 389: 622–626.

  • Itoh S, Landstrom M, Hermansson A, Itoh F, Heldin CH, Heldin NE and ten Dijke P. . 1998 J. Biol. Chem. 273: 29195–29201.

  • Ishiwata T, Friess H, Büchler MW, Lopez ME and Korc M. . 1998 Am. J. Pathol. 153: 213–222.

  • Kadin ME, Cavaille-Coll MW, Gertz R, Massagué J, Cheifetz S and George D. . 1994 Proc. Natl. Acad. Sci. USA 91: 6002–6006.

  • Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Sensibar JA, Kim JH, Kato M and Lee C. . 1996 Cancer Res. 56: 44–48.

  • Kleeff J and Korc M. . 1998 J. Biol. Chem. 273: 7495–7500.

  • Kleeff J, Ishiwata T, Friess H, Büchler MW and Korc M. . 1998 Int. J. Cancer 78: 255–260.

  • Kleeff J, Maruyama H, Friess H, Büchler MW, Falb D and Korc M. . 1999 Biochem. Biophys. Res. Com. Cancer 255: 268–273.

  • Korc M, Chandrasekar B, Yamanaka Y, Friess H, Büchler MW and Beger HG. . 1992 J. Clin. Invest. 90: 1352–1360.

  • Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P, Beger HG and Korc M. . 1998 Oncology 55: 363–369.

  • Kornmann M, Aber N and Korc M. . 1998 J. Clin. Invest. 101: 344–352.

  • Liu X, Sun Y, Constantinescu SN, Karam E, Weinberg RA and Lodish HF. . 1997 Proc. Natl. Acad. Sci. USA 90: 10669–10674.

  • MacGrogan D, Pegram M, Slamon D and Bookstein R. . 1997 Oncogene 15: 1111–1114.

  • Maesawa C, Tamura G, Nishizuka S, Iwaya T, Ogasawara S, Ishida K, Sakata K, Sato N, Ikeda K, Kimura Y, Saito K and Satodate R. . 1997 Jpn. J. Cancer Res. 88: 340–343.

  • Markowitz S, Wang J, Meyeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, Brattain M and Wilson JKV. . 1995 Science 268: 1336–1338.

  • Massagué J. . 1998 Ann. Rev. Biochem. 67: 753–791.

  • Okamoto A, Jiang W, Kim SJ, Spillare EA, Stoner GD, Weinstein IB and Harris CC. . 1994 Proc. Natl. Acad. Sci. USA 91: 11576–80.

  • Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB and Sporn MB. . 1994 Proc. Natl. Acad. Sci. USA 91: 8772–8776.

  • Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P and Massague J. . 1994 Cell 78: 59–66.

  • Raitano AB and Korc M. . 1990 J. Biol. Chem. 265: 10466–10472.

  • Reiss M. . 1997 Oncol. Res. 9: 447–457.

  • Reynisdottir I, Polyak K, Iavarone A and Massague J. . 1995 Genes Dev. 9: 1831–1845.

  • Riggins GJ, Kinzler KW, Vogelstein B and Thiagalingam S. . 1997 Cancer Res. 57: 2578–2580.

  • Saitoh M, Nishitoh H, Amagasa T, Miyazono K, Takagi M and Ichijo H. . 1996 J. Biol. Chem. 271: 2769–2775.

  • Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero Jr, RA, Meltzer PS, Hahn SA and Kern SE. . 1996 Cancer Res. 56: 2527–2530.

  • Sporn MB and Roberts AB. . 1992 J. Cell Biol. 119: 1017–1021.

  • Topper JN, Cai J, Falb D and Gimbrone Jr MA. . 1996 Proc. Natl. Acad. Sci. USA 93: 10417–10422.

  • Topper JN, Cai J, Qui Y, Anderson KR, Xu Y, Deeds J, Feeley R, Wolf B, Gimeno C, Sampson BA, Schoen FJ, Gimbrone Jr MA and Falb D. . 1997 Proc. Natl. Acad. Sci. USA 94: 9314–9319.

  • Venkatasubbarao K, Ahmed MM, Swiderski C, Harp C, Lee EY, McGrath P, Mohiuddin M, Strodel W and Freeman JW. . 1998 Genes Chrom. Cancer 22: 138–144.

  • Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G, deVillalonga P, Agell N, Lluis F, Bachs O and Capella G. . 1998 Oncogene 17: 1969–1978.

  • Wagner M, Kleeff J, Lopez ME, Bockmann I, Massagué J and Korc M. . 1998 Int. J. Cancer 78: 255–260.

  • Waltz DA, Natkin LR, Fujita RM, Wei Y and Chapman HA. . 1997 J. Clin. Invest. 100: 58–67.

  • Wang J, Han W, Zborowska E, Liang J, Wang X, Willson JKV, Sun L and Brattain MG. . 1996 J. Biol. Chem. 271: 17366–17371.

  • Warshaw AL and Fernandez-del Castillo C. . 1992 N. Engl. J. Med. 326: 455–465.

  • White RL. . 1998 Cell 92: 591–592.

  • Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF and Massagué J. . 1992 Cell 71: 1003–1014.

  • Yamamoto H, Ueno H, Ooshima A and Takeshita A. . 1996 J. Biol. Chem. 271: 16253–16259.

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Acknowledgements

This work was supported by US Public Health Service Grants CA-75059 to M Korc. J Kleef was the recipient of a fellowship award from the University of California Research and Education Grant on Gene Therapy for Cancer.

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Kleeff, J., Ishiwata, T., Maruyama, H. et al. The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18, 5363–5372 (1999). https://doi.org/10.1038/sj.onc.1202909

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