Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis

Oncogene volume 21, pages 217–226 (2002)Cite this article

Abstract

Hepatocyte Growth Factor/Scatter Factor (HGF/SF) mediates a wide variety of cellular responses by acting through the Met tyrosine kinase receptor. Inappropriate expression of HGF/SF and/or Met has been found in most types of solid tumors and is often associated with poor prognosis. Importantly, constitutional and sporadic activating mutations in Met have been discovered in human papillary renal carcinomas and other cancers, while autocrine and paracrine signaling of this receptor/ligand pair has been shown to contribute to tumorigenesis and metastasis. Numerous downstream signaling molecules have been implicated in HGF/SF-Met mediated tumorigenesis and metastasis. Stat3 is a downstream signaling molecule activated by HGF/SF-Met signaling, and is reported to contribute to cell transformation induced by a diverse set of oncoproteins. Stat3 is constitutively activated in many primary tumors and tumor cell lines, suggesting that signaling by this molecule may be important for cell transformation. To address whether Stat3 is required for HGF/SF-Met mediated tumorigenesis and metastasis, we introduced a dominant-negative form of Stat3, Stat3β into the human leiomyosarcoma cell line SK-LMS-1. We found that Stat3β has no effect on the transformed morphology, proliferation, invasion or branching morphogenesis in vitro. By contrast, expression of Stat3β affected HGF/SF-Met mediated anchorage-independent colony formation and prevented tumorigenic growth in athymic nu/nu mice. Thus, Met signaling through Stat3 provides an essential function for tumorigenic growth, which is manifested in vitro by loss of anchorage-independent growth.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Besser D, Bromberg JF, Darnell Jr JE, Hanafusa H . 1999 Mol. Cell. Biol. 19: 1401–1409

  • Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C . 1995 Nature 376: 768–771

  • Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM . 1998 Nature 391: 285–288

  • Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA . 1991 Science 251: 802–804

  • Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2488

  • Bromberg JF, 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

  • Bussolino F, Di RM, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM . 1992 J. Cell Biol. 119: 629–641

  • 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

  • Cortner J, Vande Woude GF, Rong S . 1995 The Met-HGF/SF autocrine signaling mechanism is involved in sarcomogenesis Basel/Switzerland: Birkhauser Verlag

    Google Scholar 

  • Decker T, Kovarik P . 2000 Oncogene 19: 2628–2637

  • Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G, Comoglio PM . 2000 Oncogene 19: 1547–1555

  • Faletto DL, Kaplan DR, Halverson DO, Rosen EM, Vande Woude GF . 1993 EXS 65: 107–130

  • Fan S, Ma YX, Wang JA, Yuan RQ, Meng Q, Cao Y, Laterra JJ, Goldberg ID, Rosen EM . 2000 Oncogene 19: 2212–2223

  • Fixman ED, Fournier TM, Kamikura DM, Naujokas MA, Park M . 1996 J. Bio. Chem. 271: 13116–13122

  • Gherardi E, Stoker M . 1991 Cancer Cells 3: 227–232

  • Giordano S, Di RM, Narsimhan RP, Tamagnone L, Gerbaudo EV, Chiado-Piat L, Comoglio PM . 1988 J Cell Biochem. 38: 229–236

  • Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickloff BJ, Kinsella JL, Polverini P, Rosen EM . 1993 Proc. Natl. Acad. Sci. USA 90: 1937–1941

  • Graziani A, Gramaglia D, Cantley LC, Comoglio PM . 1991 J. Biol. Chem. 266: 22087–22090

  • Jakubczak JL, LaRochelle WJ, Merlino G . 1998 Mol. Cell. Biol. 18: 1275–1283

  • Jeffers M, Fiscella M, Webb CP, Anver M, Koochekpour S, Vande Woude GF . 1998 Proc. Natl. Acad. Sci. USA 95: 14417–14422

  • Jeffers M, Rong S, Vande Woude GF . 1996 Mol. Cell. Biol. 16: 1115–1125

  • Khwaja A, Lehmann K, Marte BM, Downward J . 1998 J. Biol. Chem. 273: 18793–18801

  • Koochekpour S, Jeffers M, Rulong S, Klineberg E, Taylor G, Hudson EA, Resau JH, Vande Woude GF . 1997 Cancer Res. 57: 5391–5398

  • Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, Schmidt L, Zbar B, Vande Woude GF . 2000 Oncogene 19: 4947–4953

  • Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R . 1997 Genes Dev. 11: 3341–3350

  • Matsumoto K, Nakamura T . 1993 Hepatocyte Growth Factor-Scatter Factor and the Met Receptor Vol. 65: Goldberg, I.D. and Rosen, E.M. (eds) Basel, Switzerland: Birkhauser-Verlag pp. 225–250

    Google Scholar 

  • Niu G, Heller R, Catlett-Falcone R, Coppola D, Jaroszeski M, Dalton W, Jove R, Yu H . 1999 Cancer Res. 59: 5059–5063

  • Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Archer C, Rosen EM, Madara JL . 1994 J. Clin. Invest. 93: 2056–2065

  • Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Park S, Zhuang Z, Schmidt L, Zbar B, Lee JY . 1999 Cancer Res. 59: 307–310

  • Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG, Comoglio PM . 1995 Oncogene 10: 1631–1638

  • Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM . 1994 Cell 77: 261–271

  • Rahimi N, Hung W, Tremblay E, Saulnier R, Elliott B . 1998 J. Biol. Chem. 273: 33714–33721

  • Reddy EP, Korapati A, Chaturvedi P, Rane S . 2000 Oncogene 19: 2532–2547

  • Redley AJ, Comoglio PM, Hall A . 1995 Mol. Cell. Biol. 15: 1110–1122

  • Rodrigues GA, Park M, Schlessinger J . 1997 EMBO J. 16: 2634–2645

  • Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF . 1992 Mol. Cell. Biol. 12: 5152–5158

  • Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskarsson M, Vande Woude GF . 1993 Cancer Res. 53: 5355–5360

  • Rong S, Segal S, Anver M, Resau JH, Vande Woude GF . 1994 Proc. Natl. Acad. Sci. USA 91: 4731–4735

  • Royal I, Lamarche-Vane N, Lamorte L, Kaibuchi K, Park M . 2000 Mol. Cell. Biol. 11: 1709–1725

  • Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, Yoshikawa K, Akira S, Takeda J . 1999 EMBO J. 18: 4657–4668

  • Santoro MM, Collesi C, Grasend S, Gaudino G, Comoglio PM . 1996 Mol. Cell. Biol. 16: 7072–7083

  • Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C . 1995 Nature (London) 373: 699–702

  • Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allilmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJM, Walter MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B . 1997 Nat. Genet. 16: 68–73

  • Sonnenberg E, Meyer D, Weidner KM, Birchmeier C . 1993 J. Cell Biol. 123: 223–235

  • Southern PJ, Berg P . 1982 J. Mol. Appl. Genet. 1: 327–341

  • Stoker M, Gherardi E, Perryman M, Gray J . 1987 Nature (London) 327: 239–242

  • Streit A, Stern CD, Thery C, Ireland GW, Aparicio S, Sharpe MJ, Gherardi E . 1995 Development 121: 813–824

  • Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA, Merlino G . 1997 Proc. Natl. Acad. Sci. USA 94: 701–706

  • Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . 1998 Mol. Cell. Biol. 18: 2545–2552

  • Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S, Jove R . 1999 Mol. Cell. Biol. 19: 7519–7528

  • Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N . 1995 Nature (London) 373: 702–705

  • Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J . 1997 CIBA Found. Symp.: Plasminogen-Related Growth Factors Vol. 212: Bock GR and Goode JA (eds) West Sussex: John Wiley & Sons Ltd pp. 119–132

    Google Scholar 

  • Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM . 2001 J. Cell Biol. 153: 1023–1033

  • Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . 1996 Nature 384: 173–176

  • Weidner KM, Sachs M, Birchmeier W . 1993 J. Cell Biol. 121: 145–154

  • Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR . 2001 Proc. Natl. Acad. Sci. USA 98: 247–252

  • Zong CS, Zeng L, Jiang Y, Sadowski HB, Wang LH . 1998 J. Biol. Chem. 273: 28065–28072

Download references

Acknowledgements

We thank Brian Cao for providing anti-HGF/SF neutralizing antibody, James Resau and Eric Hudson for confocal microscope images, Dawna Dylewski, Jason Martin and Bryn Eagleson for helping on the animal study (Van Andel Research Institute). We thank the Van Andel Institute for their financial support.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, 49503, Michigan, MI, USA

    Yu-Wen Zhang, Ling-Mei Wang & George F Vande Woude

  2. Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida, 33612, FL, USA

    Richard Jove

Authors
  1. Yu-Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling-Mei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Jove
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George F Vande Woude
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George F Vande Woude.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, YW., Wang, LM., Jove, R. et al. Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21, 217–226 (2002). https://doi.org/10.1038/sj.onc.1205004

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205004

Keywords

This article is cited by

Search

Advanced search

Quick links