Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma

Changxue Lu, X. Zhu, M. C. Willingham, S. Y. Cheng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2007-2016
Number of pages10
JournalOncogene
Volume31
Issue number16
DOIs
StatePublished - Apr 19 2012
Externally publishedYes

Fingerprint

Follicular Adenocarcinoma
Thyroid Hormones
Cell Proliferation
Neoplasms
Thyroid Gland
Thyroid Neoplasms
Carcinogenesis
Catenins
Thyrotropin
Bromodeoxyuridine
Thyroid Hormone Resistance Syndrome
Cyclin D2
Propylthiouracil
Thyroid Hormone Receptors
Endocrine System
Matrix Metalloproteinase 2

Keywords

  • animal model
  • follicular thyroid carcinoma
  • protein kinase B/AKT
  • PTEN
  • thyroid hormone

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma. / Lu, Changxue; Zhu, X.; Willingham, M. C.; Cheng, S. Y.

In: Oncogene, Vol. 31, No. 16, 19.04.2012, p. 2007-2016.

Research output: Contribution to journalArticle

Lu, Changxue ; Zhu, X. ; Willingham, M. C. ; Cheng, S. Y. / Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma. In: Oncogene. 2012 ; Vol. 31, No. 16. pp. 2007-2016.
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