scholarly journals Lack of Mutations in the Thyroid Hormone Receptor (TR) α and β Genes but Frequent Hypermethylation of the TRβ Gene in Differentiated Thyroid Tumors

2007 ◽  
Vol 92 (12) ◽  
pp. 4766-4770 ◽  
Author(s):  
Biju Joseph ◽  
Meiju Ji ◽  
Dingxie Liu ◽  
Peng Hou ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Cell ◽  
Gene Mutation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Thyroid Tumor ◽  
Thyroid Tumors ◽  
Tumor Cell Lines ◽  
Thyroid Adenomas

Abstract Context: It remains inconclusive whether mutations in thyroid hormone receptor (TR) genes naturally occur in thyroid cancer and whether these genes could be suppressors of this cancer. Objectives: Our objectives were to examine further mutations of TRα and TRβ genes in thyroid cancer and also to examine their methylation as an epigenetic silencing mechanism in thyroid cancer. Experimental Design: Instead of using a cDNA sequencing approach used in previous studies, we used genomic DNA to sequence directly the coding regions of the TRα and TRβ genes to search mutations in various differentiated thyroid tumors and used methylation-specific PCR to analyze promoter methylation of these genes. Allelic zygosity status at TRβ was also analyzed. Results: We found no TRα gene mutation in 17 papillary thyroid cancers (PTCs) and 11 follicular thyroid cancers (FTCs), and no TRβ gene mutation in 16 PTCs and 12 FTCs. We also found no methylation of the TRα gene in 33 PTCs, 31 FTCs, 20 follicular thyroid adenomas (FTAs), and 10 thyroid tumor cell lines. In contrast, we found hypermethylation of the TRβ gene in 10 of 29 (34%) PTCs, 22 of 27 (81%) FTCs, five of 20 (25%) follicular thyroid adenomas, and three of 10 (30%) thyroid tumor cell lines, with the highest prevalence in FTC. We additionally examined loss of heterozygosity at TRβ and found it in three of nine (33%) PTCs and three of nine (33%) FTCs. Conclusions: Mutation is not common in TR genes, whereas hypermethylation of the TRβ gene as an alternative gene silencing mechanism is highly prevalent in thyroid cancer, particularly FTC, consistent with a possible tumor suppressor role of this gene for FTC.

scholarly journals Role of TSH in the Spontaneous Development of Asymmetrical Thyroid Carcinoma in Mice with a Targeted Mutation in a Single Allele of the Thyroid Hormone-β Receptor

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 5090-5100 ◽  
Author(s):  
Li Zhao ◽  
Xuguang Zhu ◽  
Jeong Won Park ◽  
Laura Fozzatti ◽  
Mark Willingham ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Mouse Model ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Thyroid Tumor ◽  
Human Thyroid ◽  
Migration And Invasion ◽  
Wild Type ◽  
Single Allele

Abstract Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (ThrbPV/PV mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the ThrbPV/PV mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous ThrbPV/+ mouse with mildly elevated TSH (∼2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in ThrbPV/+ mice under stimulation by high TSH. ThrbPV/+ mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. ThrbPV/+mice treated with PTU (ThrbPV/+-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of ThrbPV/+-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of ThrbPV/+-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the ThrbPV/+-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.

scholarly journals Thyroid hormone receptor β mutations in the ‘hot-spot region’ are rare events in thyroid carcinomas

2007 ◽  
Vol 192 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Ana Sofia Rocha ◽  
Ricardo Marques ◽  
Inês Bento ◽  
Ricardo Soares ◽  
João Magalhães ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hot Spot ◽  
Direct Sequencing ◽  
Human Thyroid ◽  
Thyroid Hormone Receptor Β

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor β (THRB)PV mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7–10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.

Status and expression of thep16INK4 gene in human thyroid tumors and thyroid-tumor cell lines

1996 ◽  
Vol 67 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Viola Calabr� ◽  
Maria Strazzullo ◽  
Girolama La Mantia ◽  
Monica Fedele ◽  
Christian Paulin ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Thyroid Tumor ◽  
Human Thyroid ◽  
Thyroid Tumors ◽  
Tumor Cell Lines

scholarly journals Reactivation of the Silenced Thyroid Hormone Receptor β Gene Expression Delays Thyroid Tumor Progression

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 25-35 ◽  
Author(s):  
Won Gu Kim ◽  
Xuguang Zhu ◽  
Dong Wook Kim ◽  
Lisa Zhang ◽  
Electron Kebebew ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Promoter Methylation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Lymph Node Staging ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

That a knock-in mouse harboring a dominant-negative thyroid hormone receptor (TR)-β (Thrb) mutation develops metastatic thyroid cancer strongly suggests the involvement of TRβ in carcinogenesis. Epigenetic silencing of the THRB gene is common in human cancers. The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer (DTC) and how reexpression of the THRB gene attenuated the cancer phenotypes. We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues. Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5′-aza-2′-deoxycytidine (5′-aza-CdR) and zebularine to evaluate their impact on the cancer cell phenotypes. THRB mRNA expression in DTC was 90% lower than in normal controls, and this decrease was associated with a higher tumor/lymph node staging. The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene. Treatment of FTC-236 cells with 5′-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration. FTC-236 cells stably expressing TRβ exhibited lower cell proliferation and migration through inhibition of β-catenin signaling pathways compared with FTC-236 without TRβ. 5′-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies. These finding indicate that TRβ is a tumor suppressor and could be tested as a potential therapeutic target.

scholarly journals Gelsolin: A Novel Thyroid Hormone Receptor-β Interacting Protein that Modulates Tumor Progression in a Mouse Model of Follicular Thyroid Cancer

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1306-1312 ◽  
Author(s):  
Caroline S. Kim ◽  
Fumihiko Furuya ◽  
Hao Ying ◽  
Yasuhito Kato ◽  
John A. Hanover ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cell Motility ◽  
Tumor Progression ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Metastatic Potential ◽  
Physical Interaction ◽  
Follicular Thyroid Cancer ◽  
Thyroid Hormone Receptor Β

Follicular thyroid cancer (FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant thyroid hormone receptor-β (TRβPV/PV mouse) that spontaneously develops thyroid cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TRβPV/PV mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TRβPV/PV mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor (trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TRβ1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of thyroid carcinogenesis.

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