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Updated: Jun 21, 2026
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice
Sayuri Hoshi1, Nobuo Hoshi, Minoru Okamoto
1Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional hypomorphic mice were previously developed in which Nkx2-1 gene expression is lost in 50% of the thyroid cells. Using this mouse line as compared with wild-type and Nkx2-1 heterozygous mice, a thyroid carcinogenesis study was carried out using the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN), followed by sulfadimethoxine (SDM) or the non-genotoxic carcinogen amitrole (3-amino-1,2,4-triazole). A significantly higher incidence of adenomas was obtained in Nkx2-1-thyroid-conditional hypomorphic mice as compared with the other two groups of mice only when they were treated with DHPN + SDM, but not amitrole. A bromodeoxyuridine incorporation study revealed that thyroids of the Nkx2-1-thyroid-conditional hypomorphic mice had >2-fold higher constitutive cell proliferation rate than the other two groups of mice, suggesting that this may be at least partially responsible for the increased incidence of adenoma in this mouse line after genotoxic carcinogen exposure. Thus, NKX2-1 may function to control the proliferation of thyroid follicular cells following damage by a genotoxic carcinogen.
Insights
NKX2-1 transcription factor loss in 50% of thyroid cells increases adenoma incidence after genotoxic carcinogen exposure. This suggests NKX2-1 controls thyroid cell proliferation following DNA damage.
Area of Science:
- Endocrinology
- Molecular Biology
- Carcinogenesis
Background:
- NKX2-1 is a crucial homeodomain transcription factor for thyroid development and gene expression.
- Nkx2-1-thyroid-conditional hypomorphic mice models exhibit partial loss of NKX2-1 expression in thyroid cells.
Purpose of the Study:
- To investigate the role of NKX2-1 in thyroid carcinogenesis using a genotoxic and a non-genotoxic carcinogen.
- To determine if reduced NKX2-1 expression impacts thyroid follicular cell proliferation and tumor formation.
Main Methods:
- A thyroid carcinogenesis study utilizing Nkx2-1-thyroid-conditional hypomorphic mice, wild-type, and heterozygous littermates.
- Treatment with the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN) followed by sulfadimethoxine (SDM), or the non-genotoxic carcinogen amitrole.
- Bromodeoxyuridine incorporation assays to assess cell proliferation rates.
Main Results:
- A significantly higher incidence of thyroid adenomas was observed in hypomorphic mice treated with DHPN + SDM compared to control groups.
- No significant difference in adenoma incidence was found when mice were treated with amitrole.
- Thyroid follicular cells in hypomorphic mice exhibited a >2-fold higher constitutive proliferation rate.
Conclusions:
- Reduced NKX2-1 expression in thyroid cells predisposes to adenoma formation following exposure to genotoxic carcinogens.
- NKX2-1 plays a significant role in regulating thyroid follicular cell proliferation, particularly after genotoxic insult.
- These findings highlight NKX2-1's function in maintaining thyroid homeostasis and preventing tumorigenesis.
