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PMID: 18258752 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway.

Genes & development ·Vol. 22 ·No. 4 ·2008-02-15 ·Pages 449-62

de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A

Abstract

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 beta (LIFRbeta)-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.

MeSH Terms
Animals Brain Neoplasms/metabolism,pathology Cell Nucleus/metabolism Cell Transformation, Neoplastic Cells, Cultured Chromatin Immunoprecipitation Collagen/metabolism Drug Combinations ErbB Receptors/metabolism Forkhead Box Protein O3 Forkhead Transcription Factors/metabolism Genes, Tumor Suppressor Glioblastoma/metabolism,pathology Humans Immunoblotting Immunoenzyme Techniques Laminin/metabolism Leukemia Inhibitory Factor Receptor alpha Subunit/genetics,metabolism Mice Mice, Knockout Mice, SCID PTEN Phosphohydrolase/physiology Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Plasmids Proteoglycans/metabolism Proto-Oncogene Proteins c-akt/physiology STAT3 Transcription Factor/genetics,metabolism Signal Transduction
Chemicals
Drug Combinations Forkhead Box Protein O3 Forkhead Transcription Factors FoxO3 protein, mouse Laminin Leukemia Inhibitory Factor Receptor alpha Subunit Lifr protein, mouse Proteoglycans STAT3 Transcription Factor Stat3 protein, mouse epidermal growth factor receptor VIII matrigel Collagen Phosphatidylinositol 3-Kinases ErbB Receptors Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Pten protein, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
de la Iglesia Núria
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Konopka Genevieve
Puram Sidharth V
Chan Jennifer A
Bachoo Robert M
You Mingjian J
Levy David E
Depinho Ronald A
Bonni Azad
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1606508
Published
2008-02-15
Epub
2008-00-07
Pages
449-62
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2238667
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007753 · United States
NINDS NIH HHS · NS051255 · United States
NINDS NIH HHS · R01 NS047188 · United States
NINDS NIH HHS · NS41021 · United States
NINDS NIH HHS · NS047188 · United States
NINDS NIH HHS · R01 NS041021 · United States
NINDS NIH HHS · R01 NS051255 · United States
External Links
PubMed source DOI: 10.1101/gad.1606508 PMC Full Text View journal details
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