1. Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinomaTRbetaPV/PV mice exhibit highly elevated serum thyroid-stimulating hormone (TSH) and increased thyroid hormone (TH). We have previously shown that TSH is required, but not sufficient to induce metastatic follicular thyroid cancer in TRbetaPV/PV mice. However, whether the elevated TH also contributes to the thyroid carcinogenesis of TRbetaPV/PV mice was not elucidated. To understand the role of TH in thyroid carcinogenesis, we blocked the production of TH by treating TRbetaPV/PV mice with propylthiouracil (TRbetaPV/PV-PTU mice) and compared the development of thyroid cancer in TRbetaPV/PV-PTU and untreated TRbetaPV/PV mice. We found that thyroid tumor growth was reduced 42% in TRbetaPV/PV-PTU mice as compared with TRbetaPV/PV mice. Analysis by bromodeoxyuridine (BrdU) nuclear labeling showed decreased incorporation of BrdU in thyroid tumor cells of TRbetaPV/PV-PTU mice, indicative of decreased tumor cell proliferation. However, cleaved caspase 3 staining showed no apparent changes in apoptosis of tumor cells in TRbetaPV/PV-PTU mice. Molecular studies identified a marked attenuation of the PI3K-AKT-beta-catenin signaling pathway that led to decreased protein levels of cyclin D2, thereby decreasing tumor cell proliferation in TRbetaPV/PV-PTU mice. Furthermore, matrix metalloproteinase-2, a downstream target of beta-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 TRbetaPV/PV mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of thyroid cancer. 2. SKI-606, a Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancerSrc is over-expressed or hyper-activated in a variety of human cancers including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. Therefore, the effects of a Src inhibitor, SKI-606 (bosutinib), were evaluated in a spontaneous metastatic thyroid cancer model with constitutively activated Src (TRbetaPV/PVPTEN+/- mice). TRbetaPV/PVPTEN+/- mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling. We found that SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell cycle progression. Importantly, SKI-606 dramatically prevented de-differentiation, vascular invasion, and lung metastasis of thyroid cancer cells. These responses were meditated by down-regulation of mitogen-activated protein kinase pathways and inhibition of the epithelial-mesenchymal transition. Thus, our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011191-04
Application #
8553031
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$716,979
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Park, Jeongwon; Kim, Won Gu; Zhao, Li et al. (2016) Metformin blocks progression of obesity-activated thyroid cancer in a mouse model. Oncotarget :
Zhu, Xuguang; Kim, Dong Wook; Zhao, Li et al. (2016) SAHA-induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model. Endocr Relat Cancer 23:521-33
Park, Jeong Won; Zhao, Li; Willingham, Mark C et al. (2016) Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor β. Mol Carcinog :
Park, Jeong Won; Han, Cho Rong; Zhao, Li et al. (2016) Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model. Endocr Relat Cancer 23:53-63
Zhang, Lisa J; Xiong, Yin; Nilubol, Naris et al. (2015) Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity. Carcinogenesis 36:420-8
Bassett, J H Duncan; Boyde, Alan; Zikmund, Tomas et al. (2014) Thyroid Hormone Receptor * Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice. Endocrinology 155:3699-712
Kim, Dong Wook; Park, Jeong Won; Willingham, Mark C et al. (2014) A histone deacetylase inhibitor improves hypothyroidism caused by a TR*1 mutant. Hum Mol Genet 23:2651-64
Kim, Won Gu; Zhao, Li; Kim, Dong Wook et al. (2014) Inhibition of tumorigenesis by the thyroid hormone receptor * in xenograft models. Thyroid 24:260-9
Fozzatti, Laura; Kim, Dong Wook; Park, Jeong Won et al. (2013) Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α. Proc Natl Acad Sci U S A 110:7850-5
Kim, Won Gu; Park, Jeong Won; Willingham, Mark C et al. (2013) Diet-induced obesity increases tumor growth and promotes anaplastic change in thyroid cancer in a mouse model. Endocrinology 154:2936-47

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