Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Thyroid Hormone Receptor Beta Induces a Tumor Suppressive Program in Anaplastic Thyroid Cancer

ABSTRACT: The thyroid hormone receptor beta (TRβ), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRb is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRb levels decreased tumor growth supporting the concept that TRb could function as a tumor suppressor. Yet, the TRb tumor suppression transcriptome is not well delineated and the impact of TRb is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TRb expression in the human ATC cell line SW1736 (SW-TRβ) reduces the aggressive phenotype, decreases cancer stem-cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TRβ cells via RNA-sequencing revealed distinctive expression patterns induced by ligand-bound TRβ and revealed novel molecular signaling pathways. Of note, liganded TRβ repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted pro-apoptotic pathways. Our results further revealed the JAK1-STAT1 pathway as a novel, T3-mediated, anti-tumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TRb-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TRb activation as a promising therapeutic option in cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150364 | GEO | 2020/05/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells (Adherent MCF7 cells)

Project description:Since the thyroid hormone receptor β (TRβ) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that this receptor could affect cancer stem cell biology using TRβ-expressing MCF-7 cells (MCF7-TRβ cells) treated with the thyroid hormone T3.

2019-12-05 | GSE117949 | GEO

The thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells (mammospheres from MCF7 cells)

Project description:Since the thyroid hormone receptor β (TRβ) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that this receptor could affect cancer stem cell biology using mammospheres from TRβ-expressing MCF-7 cells (MCF7-TRβ cells) treated with the thyroid hormone T3.

2019-12-05 | GSE117950 | GEO

Thyroid Hormone Dependent Transcriptional Programming by TRb Requires SWI/SNF Chromatin Remodelers

Project description:Transcriptional regulation in response to thyroid hormone (3,5,3´-triiodo-L-thyronine, T3) is a dynamic and cell-type specific process that maintains cellular homeostasis and identity in all tissues. However, our understanding of the mechanisms of thyroid hormone receptor (TR) actions at the molecular level are actively being refined. We used an integrated genomics approach to profile and characterize the cistrome of TRb, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3 in normal human thyroid cells. There are significant shifts in TRb genomic occupancy in response to T3, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers. We further demonstrate selective recruitment of BAF and PBAF SWI/SNF complexes to TRb binding sites, revealing novel differential functions in regulating chromatin accessibility and gene expression. Our findings highlight three distinct modes of TRb interaction with chromatin and coordination of coregulator activity.

2022-04-04 | PXD030403 | Pride

PIAS2b dsRNAi repression kills by mitotic catastrophe anaplastic thyroid and non-thyroid carcinomas, but not normal thyroid or differentiated carcinomas

Project description:The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with very high mortality. Double-stranded RNA–directed RNA interference (dsRNAi) targeting the PIAS2 isoform beta (PIAS2b) inhibits growth of ATC cell lines and patient primary cultures in vitro and orthotopic patient-derived xenografts (oPDX) in vivo, but not of thyroid cell lines or non-anaplastic primary thyroid cultures (differentiated carcinoma, benign lesions, or normal). PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. Strikingly, PIAS2b-dsRNAi induces mitotic catastrophe at prophase. High-throughput proteomics revealed the proteasome (PSMC5) and spindle cytoskeleton as direct targets of PIAS2b SUMOylation at mitotic initiation. PIAS2b-dsRNAi is a promising therapy for ATC and other aggressive anaplastic cancers.

2024-04-08 | PXD044110 | Pride

Resistance to thyroid hormone (RTH) and PPARa activation

Project description:In this study we used the d337T TRb transgenic mouse that has been created to reproduce the human genetic disease known as resistance to thyroid hormone (RTH) as a model to determine if the d337T TRb mutation would have an effect on PPARa activation. A single amino acid deletion (d337T) abrogates thyroid hormone (T3) binding and transforms the thyroid hormone receptor (TRb) into a constitutive repressor. The principle goal was to determine if T3 regulates myocardial energy metabolism through its nuclear receptors. We introduced a known PPARa activator (WY14, 643) into control and d337T TRb transgenic mice then examined cardiac gene expression using Affymetrix 430_2 expression arrays and RT-PCR. We compared the gene expression of PPARa, RXRb and TRa,b and three PPARa target genes among four studies groups [control, control with WY14, 643, d337T TRb, and d337T TRb with WY14, 643] consisting of seven mice per group. Microarray analysis revealed that these genes responded to the WY14, 643 treatments of control and d337T TRb mice. Analysis of the array and RT-PCR data indicates that mRNA expression levels of PPARa and mRXRb decrease after a six hour drug treatment in both control and d337T TRb mice (P<0.01) as did the array mRNA expression levels for TRa & b (P<0.025). Three target genes (AMPD3, PDK4 and UCP3) of PPARa were up regulated in control and down regulated in the d337T TRb transgenic mouse, indicating a direct action on these metabolic genes when the TRb becomes a repressor. In conclusion, PPARa activation by WY14, 643 has a positive effect on control mice and a negative effect on the TRb transgenic mice which supports our hypothesis that T3 regulates myocardial energy metabolism through its nuclear receptors. Keywords: treatment and deletion effects

2005-09-26 | GSE3067 | GEO

Transcription profiling of hearts from wild type and thyroid hormone receptor beta-mutant mice (d337T TRb) treated with or without PPARalpha activator to study the molecular effect of thyroid hormone receptor on PPARalpha activation.

2007-11-22 | E-GEOD-3067 | biostudies-arrayexpress

Expression analysis of mouse thyroid tumors

Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. We have engineered the first mouse model of ATC by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion and distant metastases. We have performed expression profiling of thyroids from control, single mutants, compound mutants, follicular tumors from Pten-/- mice, and anaplastic tumors from Pten, p53-/- mice.

2012-03-14 | E-GEOD-30427 | biostudies-arrayexpress

Expression analysis of mouse thyroid tumors

2012-03-14 | GSE30427 | GEO

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.

Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Total RNA from five murine papillary thyroid carcinoma (PTC) tumors and five murine anaplastic thyroid carcinoma (ATC) tumors was analyzed.

2014-04-02 | E-GEOD-55933 | biostudies-arrayexpress

Common Tumor Suppressive Signaling of Thyroid Hormone Receptor Beta in Breast and Thyroid Cancer Cells

Project description:The thyroid hormone receptor beta (TRβ) is a tumor suppressor in multiple types of solid tumors, most prominently in breast and thyroid cancer. An increased understanding of the molecular mechanisms by which TRβ abrogates tumorigenesis could aid in understanding the core tumor suppressive program that TRβ facilitates. Here, we introduce TRβ into the MDA-MB-468 basal-like breast cancer cell line and perform RNA-sequencing to determine changes in transcriptomic signaling. The TRβ expressing MDA-MB-468 cells exhibit a more epithelial character as determined by PCA-PAM50 score and through repression of mesenchymal cytokeratins. The epithelial to mesenchymal transition pathway is also significantly reduced. The MDA-MB-468 dataset was also compared to RNA sequencing results from the thyroid cancer line SW1736 to determine which genes are TRβ regulated across both tissue types. Stearate biosynthesis was revealed as upregulated from the shared gene set, a lipid which is known to repress breast tumorigenesis, as were chromatin remodeling pathways. These data provide novel insights into the molecular mechanisms by which TRβ suppresses breast tumorigenesis and suggests a common metabolic role in breast and thyroid cancer as well a role for TRβ in the maintenance of epithelial cellular identity.

2021-09-21 | GSE151479 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data