Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer.
Cell Line, Tumor
Cell Movement
/ genetics
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
/ physiology
Humans
Microarray Analysis
Receptor Protein-Tyrosine Kinases
/ genetics
STAT3 Transcription Factor
/ genetics
Signal Transduction
/ genetics
Thyroid Neoplasms
/ genetics
Transcription Factor Brn-3A
/ physiology
Brn3a/Pou4f1
STAT3
c-MET
thyroid cancer
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
06
11
2019
accepted:
22
05
2020
pubmed:
1
6
2020
medline:
24
2
2021
entrez:
1
6
2020
Statut:
ppublish
Résumé
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. To investigate the role of Brn3a in thyroid cancer progression and its clinical implication. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32474599
pii: 5849340
doi: 10.1210/clinem/dgaa316
pii:
doi:
Substances chimiques
POU4F1 protein, human
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Transcription Factor Brn-3A
0
RON protein
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.