STAT3 tyrosine phosphorylation influences survival in glioblastoma.
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.
Birner
Peter
P
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Toumangelova-Uzeir
Kalina
K
Natchev
Sevdalin
S
Guentchev
Marin
M
D000368:Aged; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000502:physiology; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000378:metabolism
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine
Glia. 2009 Oct;57(13):1458-67
19306372
J Clin Invest. 2002 May;109(9):1143-8
11994402
Lab Invest. 2004 Aug;84(8):941-51
15184909
Cancer Cell. 2008 Jan;13(1):69-80
18167341
J Neuropathol Exp Neurol. 2006 Dec;65(12):1181-8
17146292
Nature. 2004 Nov 18;432(7015):396-401
15549107
Anticancer Res. 1998 Jul-Aug;18(4A):2381-7
9703883
Oncogene. 2005 Nov 10;24(49):7290-300
16007122
Clin Cancer Res. 2007 Oct 1;13(19):5665-9
17908954
Cancer Res. 2003 Mar 15;63(6):1270-9
12649187
Oncogene. 2007 Apr 12;26(17):2435-44
17043651
Nat Rev Cancer. 2004 Feb;4(2):97-105
14964307
Genes Dev. 2008 Feb 15;22(4):449-62
18258752
Oncogene. 2002 Mar 27;21(13):2058-65
11960378
Clin Cancer Res. 2008 Oct 1;14(19):6042-54
18829483
Cancer Res. 2005 Jul 1;65(13):5828-34
15994959
J Immunol. 2008 Feb 15;180(4):2089-98
18250414
Mol Cancer Res. 2008 May;6(5):675-84
18505913
Nat Cell Biol. 2004 Jun;6(6):547-54
15156153
Development. 2006 Jul;133(13):2553-63
16728475
Cancer Res. 2005 Apr 1;65(7):2956-63
15805299
Cancer Cell. 2009 Apr 7;15(4):315-27
19345330
Oncogene. 2004 Apr 22;23(19):3308-16
15064729
Mol Cell Biol Res Commun. 1999 May;1(2):109-16
10356359
Stem Cells. 2009 Oct;27(10):2383-92
19658181
Neoplasma. 2008;55(6):482-7
18999875
Eur J Cancer. 2009 Mar;45(4):677-84
19121577
BMC Cancer. 2003 Sep 17;3:23
13678425
J Neurosci Res. 2002 Mar 1;67(5):670-9
11891779
Cold Spring Harb Symp Quant Biol. 1999;64:425-8
11232317
Cell Signal. 2000 Mar;12(3):143-51
10704821