title: Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.
abstract: Thyroid cancers are the most common malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid carcinogenesis, we have generated a mouse model that spontaneously develops follicular thyroid carcinoma similar to human thyroid cancer (Thrb(PV/PV) mouse). This mutant mouse harbors a dominant-negative mutated thyroid hormone receptor β (denoted PV). The PV mutation was identified in a patient with resistance to thyroid hormone (TH). Thrb(PV/PV) mice exhibit highly elevated serum thyroid-stimulating hormone levels and increased TH. We have previously shown that thyroid-stimulating hormone is required, but not sufficient to induce metastatic follicular thyroid cancer in Thrb(PV/PV) mice. However, whether the elevated TH also contributes to the thyroid carcinogenesis of Thrb(PV/PV) mice was not elucidated. To understand the role of TH in thyroid carcinogenesis, we blocked the production of TH by treating Thrb(PV/PV) mice with propylthiouracil (Thrb(PV/PV)-PTU mice) and compared the development of thyroid cancer in Thrb(PV/PV)-PTU and untreated Thrb(PV/PV) mice. We found that thyroid tumor growth was reduced by ∼42% in Thrb(PV/PV)-PTU mice as compared with Thrb(PV/PV) mice. Analysis by bromodeoxyuridine-nuclear labeling showed decreased incorporation of bromodeoxyuridine in thyroid tumor cells of Thrb(PV/PV)-PTU mice, indicative of decreased tumor cell proliferation. However, cleaved-caspase 3 staining showed no apparent changes in apoptosis of tumor cells in Thrb(PV/PV)-PTU mice. Molecular studies identified a marked attenuation of the PI3K-AKT-β-catenin signaling pathway that led to decreased protein levels of cyclin D2, thereby decreasing tumor cell proliferation in Thrb(PV/PV)-PTU mice. Furthermore, matrix metalloproteinase-2, a downstream target of β-catenin and a key regulator during tumor invasion and metastasis, was also decreased. Thus, the present study uncovers a critical role of TH in promoting the thyroid carcinogenesis of Thrb(PV/PV) mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of thyroid cancer.
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
authors: C
authors: C
authors: Lu
authors: X
authors: X
authors: Zhu
authors: M C
authors: MC
authors: Willingham
authors: S-Y
authors: SY
authors: Cheng
mesh_terms: D018263:Adenocarcinoma, Follicular; D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D056742:Cyclin D2 / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D011441:Propylthiouracil / Q000494:pharmacology; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D013963:Thyroid Hormones / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D013972:Thyrotropin / Q000097:blood
chemical_list: D013956:Antithyroid Agents; D056742:Cyclin D2; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D011441:Propylthiouracil; D013972:Thyrotropin