TY - JOUR
T1 - Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma
AU - Lu, C.
AU - Zhu, X.
AU - Willingham, M. C.
AU - Cheng, S. Y.
N1 - Funding Information:
This research was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research.
PY - 2012/4/19
Y1 - 2012/4/19
N2 - 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.
AB - 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.
KW - PTEN
KW - animal model
KW - follicular thyroid carcinoma
KW - protein kinase B/AKT
KW - thyroid hormone
UR - http://www.scopus.com/inward/record.url?scp=84859893531&partnerID=8YFLogxK
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U2 - 10.1038/onc.2011.390
DO - 10.1038/onc.2011.390
M3 - Article
C2 - 21909131
AN - SCOPUS:84859893531
SN - 0950-9232
VL - 31
SP - 2007
EP - 2016
JO - Oncogene
JF - Oncogene
IS - 16
ER -