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Published on: February 22, 2015
The T-box transcription factor brachyury behaves as a tumor suppressor in gliomas
Filipe Pinto1,2,3,4, Ângela M Costa1,2,3, Gisele C Santos5
1Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
Abstract:
The oncogene brachyury (TBXT) is a T-box transcription factor that is overexpressed in multiple solid tumors and is associated with tumor aggressiveness and poor patient prognosis. Gliomas comprise the most common and aggressive group of brain tumors, and at the present time the functional and clinical impact of brachyury expression has not been investigated previously in these neoplasms. Brachyury expression (mRNA and protein) was assessed in normal brain (n = 67), glioma tissues (n = 716) and cell lines (n = 42), and further in silico studies were undertaken using genomic databases totaling 3115 samples. Our glioma samples were analyzed for copy number (n = 372), promoter methylation status (n = 170), and mutation status (n = 1569 tissues and n = 52 cell lines) of the brachyury gene. The prognostic impact of brachyury expression was studied in 1524 glioma patient tumors. The functional impact of brachyury on glioma proliferation, viability, and cell death was evaluated both in vitro and in vivo. Brachyury was expressed in the normal brain, and significantly downregulated in glioma tissues. Loss of brachyury was associated with tumor aggressiveness and poor survival in glioma patients. Downregulation of brachyury was not associated with gene deletion, promoter methylation, or inactivating point mutations. Brachyury re-expression in glioma cells was found to decrease glioma tumorigenesis by induction of autophagy. These data strongly suggest that brachyury behaves as a tumor suppressor gene in gliomas by modulating autophagy. It is important to note that brachyury constitutes an independent positive biomarker of patient prognosis. Our findings indicate that the role of brachyury in tumorigenesis may be tissue-dependent and demands additional investigation to guide rational interventions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insights
Brachyury (TBXT) is downregulated in gliomas, acting as a tumor suppressor by inducing autophagy. Loss of brachyury correlates with aggressive tumors and poor survival, indicating its potential as a positive prognostic biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The oncogene brachyury (TBXT) is a T-box transcription factor known for its overexpression in various solid tumors, correlating with increased tumor aggressiveness and poorer patient outcomes.
- Gliomas represent the most prevalent and aggressive form of brain tumors, yet the specific role and clinical significance of brachyury expression in these neoplasms remain largely unexplored.
Purpose of the Study:
- To investigate the expression, functional, and clinical impact of brachyury (TBXT) in glioma.
- To determine if brachyury functions as an oncogene or tumor suppressor in the context of gliomas.
- To assess the prognostic value of brachyury expression in glioma patients.
Main Methods:
- Assessed brachyury expression (mRNA and protein) in normal brain tissue, glioma tissues, and cell lines.
- Performed in silico analyses using genomic databases.
- Analyzed glioma samples for gene copy number, promoter methylation, and mutation status of the brachyury gene.
- Evaluated the prognostic impact of brachyury expression in a large cohort of glioma patients.
- Assessed the functional impact of brachyury on glioma cell proliferation, viability, and cell death in vitro and in vivo.
Main Results:
- Brachyury was found to be expressed in normal brain tissue but significantly downregulated in glioma tissues.
- Loss of brachyury expression was associated with increased tumor aggressiveness and poorer patient survival.
- Downregulation of brachyury was not attributed to gene deletion, promoter methylation, or inactivating mutations.
- Re-expression of brachyury in glioma cells reduced tumorigenesis through the induction of autophagy.
- Brachyury expression was identified as an independent positive biomarker for patient prognosis.
Conclusions:
- Brachyury functions as a tumor suppressor gene in gliomas, primarily by modulating autophagy.
- The downregulation of brachyury in gliomas is linked to tumor aggressiveness and unfavorable patient prognosis.
- Brachyury represents a promising independent positive prognostic biomarker for glioma patients, warranting further investigation into its tissue-dependent role in tumorigenesis.
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