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Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma
Durmus Burgucu1, Kenan Guney, Duygu Sahinturk
1Department of Physiology, School of Medicine, Akdeniz University, Antalya 07058, Turkey.
Background:
Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression.
Methods:
Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann-Whitney, Spearman's Correlation and Wilcoxon signed-rank tests were used to analyze the data.
Results:
We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN.
Conclusions:
We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer.
Insights
Tbx3 is overexpressed in head and neck squamous cell cancer (HNSCC), repressing PTEN tumor suppressor activity. This finding reveals a new cancer mechanism and suggests Tbx3 as a potential HNSCC biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Head and neck squamous cell cancer (HNSCC) has a poor prognosis despite treatment advances.
- PTEN tumor suppressor is often downregulated in HNSCC, with low mutation rates, suggesting transcriptional repression.
- Tbx2 and Tbx3 are transcriptional repressors implicated in various cancers.
Purpose of the Study:
- To investigate the hypothesis that Tbx3 is overexpressed in HNSCC.
- To determine if Tbx3 represses PTEN expression in HNSCC.
- To explore the role of Tbx3 in HNSCC development and progression.
Main Methods:
- Immunohistochemistry and quantitative PCR (qPCR) to assess PTEN and Tbx3 levels in HNSCC tissues and adjacent normal tissues from 33 patients.
- Transfection of HeLa and HEK cell lines with Tbx3 plasmid to evaluate effects on endogenous PTEN.
- Flow cytometry and transcription assays to analyze PTEN expression and Tbx3's effect on PTEN promoter activity.
- Statistical analysis using Mann-Whitney, Spearman's Correlation, and Wilcoxon signed-rank tests.
Main Results:
- Tbx3 mRNA and protein levels were significantly increased in HNSCC tissues compared to normal tissues (p<0.001).
- PTEN mRNA and protein levels were significantly reduced in HNSCC tissues.
- Overexpression of Tbx3 in cell lines led to decreased endogenous PTEN mRNA and protein levels.
- Tbx3 was shown to repress both basal and induced PTEN promoter activity.
Conclusions:
- Tbx3 is upregulated in HNSCC tissues.
- Tbx3 directly represses PTEN transcription.
- This mechanism contributes to HNSCC formation and progression.
- Tbx3 shows potential as a biomarker for HNSCC.
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