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Published on: August 23, 2019
Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer
Seung-Nam Jung1, Yea Eun Kang2, Gun Ho Lee1
1Department of Otolaryngology-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea.
Background:
Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated.
Purpose:
To investigate the role of Brn3a in thyroid cancer progression and its clinical implication.
Methods:
We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a.
Results:
The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer.
Conclusions:
Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.
Insights
Brn3a acts as a tumor suppressor in thyroid cancer by inhibiting cell migration and invasion. This transcription factor
Area of Science:
- Molecular oncology
- Cancer biology
- Transcription factors
Background:
- Brn3a (Pou4f1) is a transcription factor found in various cancers.
- Its role in thyroid cancer progression remains uninvestigated.
Purpose of the Study:
- To investigate the role of Brn3a in thyroid cancer progression.
- To analyze the clinical implications of Brn3a in thyroid cancer.
Main Methods:
- Analyzed Brn3a expression in thyroid cancer patients using The Cancer Genome Atlas (TCGA) database.
- Performed in vitro assays (proliferation, migration, invasion) and Western blotting after Brn3a manipulation (overexpression/suppression).
Main Results:
- Brn3a promoter hypermethylation and downregulation observed in aggressive thyroid cancer.
- Low Brn3a expression correlated with aggressive phenotypes (T stage, extrathyroid extension).
- Brn3a overexpression suppressed migration/invasion by inhibiting epithelial-mesenchymal transition (EMT) and STAT3 signaling via c-MET.
- Brn3a knockdown increased migration/invasion by upregulating c-MET/STAT3.
Conclusions:
- Brn3a functions as a tumor suppressor in thyroid cancer, reducing cell migration and invasion.
- Targeting Brn3a-regulated pathways offers potential therapeutic strategies for thyroid cancer metastasis.
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