Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway
Open accessAbstract
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.
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PTEN acts as a negative regulator of STAT3 through its protein phosphatase activity, but this modulation is context dependent and PTEN can also positively regulate STAT3 in certain tumors such as gliomas.
“Other phosphatases have been implicated in the modulation of STAT3 signaling, for example, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which has both lipid and protein phosphatase activity, has been shown to act as a negative regulator of STAT3 (Sun and Steinberg, 2002; Mukhopadhyay et al., 2010), where its protein phosphatase activity negatively affects phosphorylation of”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as de la Iglesia et al., 2008
The Discussion (page unavailable) supports positive regulation in this context: PTEN loss reduces LIFRβ expression and STAT3 Tyr705 phosphorylation in astrocytes, and correlates with STAT3 inactivation in human glioblastomas. It does not support the attributed negative regulation through PTEN’s protein phosphatase activity; the mechanism it describes runs through Akt–FOXO and LIFRβ. (LLM, conf=0.88)
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The phosphoinositide 3-kinase pathway
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Identification of diverse astrocyte populations and their malignant analogs
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“However, this modulation of STAT3 activity is context dependent, as it has been shown to also positively regulate STAT3 in certain tumors such as gliomas (de la Iglesia et al., 2008).”
BackgroundSTAT3 in hepatocellular carcinoma: new perspectives
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- Authors
- de la Iglesia, N., Konopka, G., Puram, S. V., Chan, J. A., Bachoo, R. M., You, M. J., Levy, D. E., DePinho, R. A., & Bonni, A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- NYU Langone Health (US)
- Corresponding author
- Bonni, Azad
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-02-07
- Volume
- 22
- Issue
- 4
- Pages
- 449-462
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2238667
- OpenAlex
- W2170588832
- Cited by
- 336
- References
- 4
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 17 · 2022: 9 · 2021: 17 · 2020: 11 · 2019: 13 · 2018: 16 · 2017: 27 · 2016: 18 · 2015: 15 · 2014: 28 · 2013: 28 · 2012: 33
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alfred P. Sloan Foundation
- Alexander and Margaret Stewart Trust
- Giovanni Armenise-Harvard Foundation
- Fundación Ramón Areces
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Neurological Disorders and Stroke (NS 051255, R01NS047188, NS41021, R01NS051255, NS047188, R01NS041021)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- STAT3, PTEN, glioblastoma, tumor suppressor pathways, LIFR, EGFRvIII, tumor mutational profile, STAT3 inhibitor
- MeSH terms
- Forkhead Box Protein O3, Animals, Brain Neoplasms, Cell Nucleus, Cell Transformation, Neoplastic, Cells, Cultured, Collagen, Drug Combinations, Glioblastoma, Humans, Immunoenzyme Techniques, Laminin, Phosphorylation, Plasmids, Proteoglycans, Immunoblotting, Signal Transduction, Genes, Tumor Suppressor, Mice, SCID, Mice, Knockout, Phosphatidylinositol 3-Kinases, Chromatin Immunoprecipitation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Forkhead Transcription Factors, Leukemia Inhibitory Factor Receptor alpha Subunit, ErbB Receptors
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