Skip to main content

Advertisement

SpringerLink
Log in

STAT3 tyrosine phosphorylation influences survival in glioblastoma

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Signal transducer and activator of transcription protein 3 (STAT3) is a regulator of central nervous system (CNS) development and a promising therapeutic target in human cancers. Activation of STAT3 promotes oncogenesis in a variety of tissues, but knowledge of its role in glioblastoma is still limited. Recent results indicate that STAT3 acts as a tumor suppressor or an oncogene depending upon the genetic background of the tumor. Here we immunohistochemically assessed Y705-phosphorylated STAT3 (pY705-STAT3) in formalin-fixed, paraffin-embedded specimens of 111 patients with supratentorial glioblastomas and 25 patients with supratentorial grade III gliomas. We found that glioblastoma patients with high or very high numbers of pY705-STAT3-positive tumor cells had significantly shorter overall survival than those with no or low numbers (P = 0.001, Cox regression). Interestingly the proportion of grade III glioma cases with high or very high numbers of pY705-STAT3-positive tumor cells was similar to that in glioblastoma. Our findings provide evidence that activation of STAT3 by Y705 phosphorylation is linked with clinically more aggressive behavior in glioblastomas, but is most likely not associated with tumor progression of grade III gliomas. In sum, our results suggest that STAT3 inhibition should be considered as a therapeutic approach in malignant gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bromberg JF, Darnell JE Jr (1999) Potential roles of Stat1 and Stat3 in cellular transformation. Cold Spring Harb Symp Quant Biol 64:425–428

    Article  CAS  PubMed  Google Scholar 

  2. Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13:5665–5669

    Article  CAS  PubMed  Google Scholar 

  3. Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y (2004) Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 6:547–554

    Article  CAS  PubMed  Google Scholar 

  4. Levy DE, Lee CK (2002) What does Stat3 do? J Clin Invest 109:1143–1148

    CAS  PubMed  Google Scholar 

  5. Schlessinger K, Levy DE (2005) Malignant transformation but not normal cell growth depends on signal transducer and activator of transcription 3. Cancer Res 65:5828–5834

    Article  CAS  PubMed  Google Scholar 

  6. Brantley EC, Benveniste EN (2008) Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 6:675–684

    Article  CAS  PubMed  Google Scholar 

  7. Schaefer LK, Menter DG, Schaefer TS (2000) Activation of stat3 and stat1 DNA binding and transcriptional activity in human brain tumour cell lines by gp130 cytokines. Cell Signal 12:143–151

    Article  CAS  PubMed  Google Scholar 

  8. Schaefer LK, Ren Z, Fuller GN, Schaefer TS (2002) Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21:2058–2065

    Article  CAS  PubMed  Google Scholar 

  9. Wang H, Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN (2004) Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 84:941–951

    Article  CAS  PubMed  Google Scholar 

  10. Weissenberger J, Loeffler S, Kappeler A et al (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23:3308–3316

    Article  CAS  PubMed  Google Scholar 

  11. Dasgupta A, Raychaudhuri B, Haqqi T et al (2009) Stat3 activation is required for the growth of U87 cell-derived tumours in mice. Eur J Cancer 45:677–684

    Article  CAS  PubMed  Google Scholar 

  12. Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B (2009) Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia 57:1458–1467

    Article  PubMed  Google Scholar 

  13. Peñuelas S, Anido J, Prieto-Sánchez R et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15:315–327

    Article  PubMed  Google Scholar 

  14. Sherry MM, Reeves A, Wu JK, Cochran BH (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27:2383–2392

    Article  CAS  PubMed  Google Scholar 

  15. Paillaud E, Costa S, Fages C et al (2009) Retinoic acid increases proliferation rate of GL-15 glioma cells, involving activation of STAT-3 transcription factor. J Neurosci Res 67:670–679

    Article  Google Scholar 

  16. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (2003) Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63:1270–1279

    CAS  PubMed  Google Scholar 

  17. Rahaman SO, Vogelbaum MA, Haque SJ (2005) Aberrant Stat3 signaling by interleukin-4 in malignant glioma cells: involvement of IL-13Ralpha2. Cancer Res 65:2956–2963

    Article  CAS  PubMed  Google Scholar 

  18. Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23

    Article  PubMed  Google Scholar 

  19. Lo HW, Cao X, Zhu H, Ali-Osman F (2008) Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 14:6042–6054

    Article  CAS  PubMed  Google Scholar 

  20. Iwamaru A, Szymanski S, Iwado E et al (2007) A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26:2435–2444

    Article  CAS  PubMed  Google Scholar 

  21. Lee J, Son MJ, Woolard K et al (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13:69–80

    Article  CAS  PubMed  Google Scholar 

  22. Halfter H, Friedrich M, Postert C, Ringelstein EB, Stögbauer F (1999) Activation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth inhibition of human glioma cells. Mol Cell Biol Res Commun 1:109–116

    Article  CAS  PubMed  Google Scholar 

  23. Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN, Nutt CL (2006) Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival. J Neuropathol Exp Neurol 65:1181–1188

    Article  CAS  PubMed  Google Scholar 

  24. Fujita M, Zhu X, Sasaki K et al (2008) Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J Immunol 180:2089–2098

    CAS  PubMed  Google Scholar 

  25. Cattaneo E, Magrassi L, De-Fraja C et al (1998) Variations in the levels of the JAK/STAT and ShcA proteins in human brain tumors. Anticancer Res 18:2381–2387

    CAS  PubMed  Google Scholar 

  26. Ehrmann J, Strakova N, Vrzalikova K, Hezova R, Kolar Z (2008) Expression of STATs and their inhibitors SOCS and PIAS in brain tumors. In vitro and in vivo study. Neoplasma 55:482–487

    CAS  PubMed  Google Scholar 

  27. Ghosh MK, Sharma P, Harbor PC, Rahaman SO, Haque SJ (2005) PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells. Oncogene 24:7290–7300

    Article  CAS  PubMed  Google Scholar 

  28. de la Iglesia N, Konopka G, Puram SV et al (2008) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22:449–462

    Article  PubMed  Google Scholar 

  29. Yoshimatsu T, Kawaguchi D, Oishi K et al (2006) Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex. Development 133:2553–2563

    Article  CAS  PubMed  Google Scholar 

  30. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  CAS  PubMed  Google Scholar 

  31. Yu H, Jove R (2004) The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4:97–105

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Dr. Johannes Hainfellner, Vienna, for advice and critical discussions. This work was supported by European Union Social Fund Program BG051PO001/07/3.3-02 grant number 80/17.06.2008 and BSF grant number Д01-840/16.10.2007.

Author information

Authors and Affiliations

  1. Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, 1097, Vienna, Austria

    Peter Birner

  2. Laboratory of Neuropathology, St. Ivan Rilsky Hospital, 15, Akad. I. Geschov Blvd., 1431, Sofia, Bulgaria

    Kalina Toumangelova-Uzeir & Sevdalin Natchev

  3. Department of Neurosurgery, Pirogov Emergency Hospital, 21, General Eduard Totleben Blvd., 1606, Sofia, Bulgaria

    Marin Guentchev

Authors
  1. Peter Birner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalina Toumangelova-Uzeir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sevdalin Natchev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marin Guentchev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marin Guentchev.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Birner, P., Toumangelova-Uzeir, K., Natchev, S. et al. STAT3 tyrosine phosphorylation influences survival in glioblastoma. J Neurooncol 100, 339–343 (2010). https://doi.org/10.1007/s11060-010-0195-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0195-8

Keywords

Search

Navigation