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Role of TSH in the spontaneous development of asymmetrical thyroid carcinoma in mice with a targeted mutation in a single allele of the thyroid hormone-β receptor.
- Source :
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Endocrinology [Endocrinology] 2012 Oct; Vol. 153 (10), pp. 5090-100. Date of Electronic Publication: 2012 Aug 23. - Publication Year :
- 2012
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Abstract
- Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (Thrb(PV/PV) mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the Thrb(PV/PV) mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous Thrb(PV/+) mouse with mildly elevated TSH (~2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in Thrb(PV/+) mice under stimulation by high TSH. Thrb(PV/+) mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. Thrb(PV/+)mice treated with PTU (Thrb(PV/+)-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of Thrb(PV/+)-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of Thrb(PV/+)-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.
- Subjects :
- Alleles
Animals
Carcinoma pathology
Cell Proliferation
Cyclin-Dependent Kinases genetics
Mice
Mutagenesis, Site-Directed
Mutation
Signal Transduction genetics
Thyroid Hormones blood
Thyroid Neoplasms pathology
Carcinoma genetics
Thyroid Gland pathology
Thyroid Hormone Receptors beta genetics
Thyroid Neoplasms genetics
Thyrotropin genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 153
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 22919057
- Full Text :
- https://doi.org/10.1210/en.2012-1600