Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer
| Autor: | Mi Ae Lim, Yan Li Jin, Seung-Nam Jung, Yea Eun Kang, Chan Oh, Gun Ho Lee, Ho-Ryun Won, Jae Won Chang, Lihua Liu, Bon Seok Koo, Taejeong Oh, Kyung Min Lee |
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| Rok vydání: | 2020 |
| Předmět: |
STAT3 Transcription Factor
medicine.medical_specialty Epithelial-Mesenchymal Transition C-Met Endocrinology Diabetes and Metabolism Clinical Biochemistry Biochemistry Metastasis chemistry.chemical_compound Endocrinology Cell Movement Cell Line Tumor Internal medicine medicine Humans Genes Tumor Suppressor Thyroid Neoplasms STAT3 Thyroid cancer Transcription factor Transcription Factor Brn-3A biology business.industry Kinase Gene Expression Profiling Biochemistry (medical) Receptor Protein-Tyrosine Kinases Cell migration Microarray Analysis medicine.disease Gene Expression Regulation Neoplastic chemistry STAT protein biology.protein Cancer research business Signal Transduction |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 105:e3127-e3141 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/clinem/dgaa316 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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