QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data All Versions of this Article: gad.1606508v1 22/4/449    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de la Iglesia, N. Articles by Bonni, A. Search for Related Content PubMed PubMed Citation Articles by de la Iglesia, N. Articles by Bonni, A. Social Bookmarking                   What's this?

Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway

¹ Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA; ³ Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA; ⁴ Division of Neuropathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA; ⁵ Department of Medical Oncology, Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, and Department of Medicine and Department Genetics, Harvard Medical School, Boston, Massachusetts 02115 USA; ⁶ Department of Pathology and Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA

Activation of the transcription factor STAT3 is thought to potently promote oncogenesis in a variety of tissues, leading to intense efforts to develop STAT3 inhibitors for many tumors, including the highly malignant brain tumor glioblastoma. However, the function of STAT3 in glioblastoma pathogenesis has remained unknown. Here, we report that STAT3 plays a pro-oncogenic or tumor-suppressive role depending on the mutational profile of the tumor. Deficiency of the tumor suppressor PTEN triggers a cascade that inhibits STAT3 signaling in murine astrocytes and human glioblastoma tumors. Specifically, we forge a direct link between the PTEN–Akt–FOXO axis and the leukemia inhibitory factor receptor β (LIFRβ)–STAT3 signaling pathway. Accordingly, PTEN knockdown induces efficient malignant transformation of astrocytes upon knockout of the STAT3 gene. Remarkably, in contrast to the tumor-suppressive function of STAT3 in the PTEN pathway, STAT3 forms a complex with the oncoprotein epidermal growth factor receptor type III variant (EGFRvIII) in the nucleus and thereby mediates EGFRvIII-induced glial transformation. These findings indicate that STAT3 plays opposing roles in glial transformation depending on the genetic background of the tumor, providing the rationale for tailored therapeutic intervention in glioblastoma.

[Keywords: STAT3; astrocyte; glioblastoma; PTEN; EGFRvIII]]

Received August 17, 2007; revised version accepted December 7, 2007.

⁸ Corresponding author.

E-MAIL azad_bonni{at}hms.harvard.edu; FAX (617) 432-4101.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1606508

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. Gabriely, T. Wurdinger, S. Kesari, C. C. Esau, J. Burchard, P. S. Linsley, and A. M. Krichevsky MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators Mol. Cell. Biol., September 1, 2008; 28(17): 5369 - 5380. [Abstract] [Full Text] [PDF]

				E. C. Brantley, L. B. Nabors, G. Y. Gillespie, Y.-H. Choi, C. A. Palmer, K. Harrison, K. Roarty, and E. N. Benveniste Loss of Protein Inhibitors of Activated STAT-3 Expression in Glioblastoma Multiforme Tumors: Implications for STAT-3 Activation and Gene Expression Clin. Cancer Res., August 1, 2008; 14(15): 4694 - 4704. [Abstract] [Full Text] [PDF]

				N. de la Iglesia, G. Konopka, K.-L. Lim, C. L. Nutt, J. F. Bromberg, D. A. Frank, P. S. Mischel, D. N. Louis, and A. Bonni Deregulation of a STAT3-Interleukin 8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness J. Neurosci., June 4, 2008; 28(23): 5870 - 5878. [Abstract] [Full Text] [PDF]