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

C. 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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma'. Together they form a unique fingerprint.

  • Cite this