| First Author | Zhao L | Year | 2012 |
| Journal | Endocrinology | Volume | 153 |
| Issue | 10 | Pages | 5090-100 |
| PubMed ID | 22919057 | Mgi Jnum | J:192946 |
| Mgi Id | MGI:5466838 | Doi | 10.1210/en.2012-1600 |
| Citation | Zhao L, et al. (2012) 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-beta receptor. Endocrinology 153(10):5090-100 |
| abstractText | Mutations of the thyroid hormone receptor-beta gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-beta 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. |
