Thyroid hormone receptor-mediated regulation of the methionine adenosyltransferase 1 gene is associated with cell invasion in hepatoma cell lines

2010 ◽  
Vol 67 (11) ◽  
pp. 1831-1843 ◽  
Author(s):  
Sheng-Ming Wu ◽  
Ya-Hui Huang ◽  
Yi-Hsin Lu ◽  
Ling-Fang Chien ◽  
Chau-Ting Yeh ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cell Lines ◽  
Cell Invasion ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hepatoma Cell ◽  
Methionine Adenosyltransferase ◽  
Hepatoma Cell Lines

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.

scholarly journals Overexpression of thyroid hormone receptor beta1 is associated with thyrotropin receptor gene expression and proliferation in a human thyroid carcinoma cell line

2000 ◽  
Vol 165 (2) ◽  
pp. 379-389 ◽  
Author(s):  
ST Chen ◽  
HY Shieh ◽  
JD Lin ◽  
KS Chang ◽  
KH Lin
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Thyroid Hormone ◽  
Cell Line ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Human Thyroid ◽  
Thyrotropin Receptor ◽  
Tshr Gene

To correlate the differentiation phenotype of two human thyroid cancer cell lines with their expression of various molecular markers, we analyzed the mRNA levels of four thyroid-specific genes, including thyrotropin receptor (TSHR), thyroglobulin (Tg), thyroid transcription factor-1 (TTF-1), and paired-box containing transcription factor-8 (PAX-8) genes. The results showed a differentiation-status-related pattern in which a well-differentiated cell line (WRO) expressed all the four genes, in contrast to an anaplastic cell line (ARO) that expressed TTF-1 and reduced levels of TSHR, but no Tg or PAX-8 genes. Furthermore, to verify the finding of concomitant loss of beta subtype thyroid hormone receptor (TRbeta) and TSHR gene expression in neoplastic thyroid tumors (Bronnegard et al. 1994), we examined the expression levels of TRbeta1 gene in these cell lines. Whereas the WRO cells produced an abundant amount of TRbeta1 protein detectable by immunoprecipitation, the ARO cells produced none. This new observation prompted us to investigate whether overexpression of TRbeta1 protein in ARO cells might produce changes in the differentiation phenotypes. We found that the level of expression of the TSHR gene and the proliferative index of ARO cells were significantly upregulated in the cells stably transfected with wild-type TRbeta1. These findings suggest that TRbeta1 protein overexpression can affect the differentiation phenotypes and induce more efficient cell proliferation of the anaplastic ARO cells.

Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4

2013 ◽  
Vol 439 (1) ◽  
pp. 60-65 ◽  
Author(s):  
Hsiang-Cheng Chi ◽  
Chen-Hsin Liao ◽  
Ya-Hui Huang ◽  
Sheng-Ming Wu ◽  
Chung-Ying Tsai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hepatoma Cell

scholarly journals Thyroid Hormone Receptor β (THRB) Is a Major Target Gene for MicroRNAs Deregulated in Papillary Thyroid Carcinoma (PTC)

2011 ◽  
Vol 96 (3) ◽  
pp. E546-E553 ◽  
Author(s):  
Krystian Jazdzewski ◽  
Joanna Boguslawska ◽  
Jaroslaw Jendrzejewski ◽  
Sandya Liyanarachchi ◽  
Janusz Pachucki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Untranslated Region ◽  
Normal Tissue ◽  
Thyroid Hormone Receptor ◽  
Papillary Thyroid ◽  
Down Regulation

Context: Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors. Objective: Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC. Design: The potential binding of miR to the 3′-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3′-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs. Results: THRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37–48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10–28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32–66%, P < 0.0034 and up-regulation of 48–57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs. Conclusions: MiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.

scholarly journals Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer cell lines via genomic mechanisms

2021 ◽  
Author(s):  
Cole D Davidson ◽  
Eric L Bolf ◽  
Noelle E Gillis ◽  
Lauren M Cozzens ◽  
Jennifer A Tomczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Regulatory Subunit ◽  
Pi3k Signaling ◽  
Receptor Beta

Abstract Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85⍺. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.

scholarly journals Thyroid Hormone Promotes Cell Invasion through Activation of Furin Expression in Human Hepatoma Cell Lines

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 3817-3831 ◽  
Author(s):  
Ruey-Nan Chen ◽  
Ya-Hui Huang ◽  
Ya-Chu Lin ◽  
Chau-Ting Yeh ◽  
Ying Liang ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Lung Tumor ◽  
Hepatoma Cell ◽  
Matrix Metalloproteinase 2 ◽  
Human Hepatoma Cell ◽  
Hepatoma Cell Lines ◽  
Deficient Mice

The objective of this study was to identify genes regulated by thyroid hormone (T3) and associated with tumor invasion. The gene encoding furin, as previously identified by cDNA microarray, is known to be up-regulated by T3 treatment, and stimulated furin production occurs in thyroidectomized rats after administration of T3. Presently, by using serial deletion of the promoter and EMSAs, the T3 response element on the furin promoter was localized to the −6317/−6302 region. T3-mediated furin up-regulation was cooperative with TGF-β because T3 induction increased after Smad3/4 addition. Furthermore, the invasiveness of HepG2-thyroid hormone receptor (TR) cells was significantly increased by T3 treatment, perhaps due to furin processing of matrix metalloproteinase-2 and -9. In addition, furin up-regulation either by stable overexpression or T3 and/or TGF-β induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TRα1 cells. The HepG2-furin mice displayed a higher metastasis index and tumor size than HepG2-neo mice. Notably, the increased liver and lung tumor number or size in the hyperthyroid severe-combined immune-deficient mice as well as TGF-β mice was attributed specifically to furin overexpression in the HepG2-TRα1 cells. Furthermore, this study demonstrated that furin overexpression in some types of hepatocellular carcinomas is TR dependent and might play a crucial role in the development of hepatocellular carcinoma. Thus, T3 regulates furin gene expression via a novel mechanism or in cooperation with TGF-β to enhance tumor metastasis in vitro and in vivo.

scholarly journals Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells

Hepatology ◽  
2012 ◽  
Vol 55 (3) ◽  
pp. 910-920 ◽  
Author(s):  
Chen-Hsin Liao ◽  
Chau-Ting Yeh ◽  
Ya-Hui Huang ◽  
Sheng-Ming Wu ◽  
Hsiang-Cheng Chi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cell Invasion ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hepatoma Cells ◽  
Human Hepatoma ◽  
Human Hepatoma Cells

scholarly journals A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents

2021 ◽  
Author(s):  
Noelle E Gillis ◽  
Cole D Davidson ◽  
Lauren M Cozzens ◽  
Emily R Wilson ◽  
Eric L Bolf ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Agents ◽  
Selective Activation ◽  
Aggressive Phenotype ◽  
Receptor Beta

Background: Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TRβ) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TRβ with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics. Methods: We used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined. Results: Our results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells. Conclusion: Activation of TRβ with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.

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