scholarly journals Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

2013 ◽  
Vol 21 (2) ◽  
pp. 161-173 ◽  
Author(s):  
Zongjing Zhang ◽  
Dingxie Liu ◽  
Avaniyapuram Kannan Murugan ◽  
Zhimin Liu ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Histone Acetylation ◽  
Underlying Mechanism ◽  
Histone Deacetylation ◽  
Braf V600e ◽  
Epigenetic Mechanism ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Rat Thyroid

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.

scholarly journals AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 785 ◽  
Author(s):  
Francesca Collina ◽  
Lucia La Sala ◽  
Federica Liotti ◽  
Nella Prevete ◽  
Elvira La Mantia ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Braf V600e ◽  
Specific Gene ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Viral Oncogene ◽  
Rat Thyroid ◽  
Viral Oncogene Homolog

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

scholarly journals Trace Amine-Associated Receptor 1 Trafficking to Cilia of Thyroid Epithelial Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1518
Author(s):  
Maria Qatato ◽  
Vaishnavi Venugopalan ◽  
Alaa Al-Hashimi ◽  
Maren Rehders ◽  
Aaron D. Valentine ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Human Thyroid ◽  
Apical Plasma Membrane ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Trace Amine ◽  
Rat Thyroid

Trace amine-associated receptor 1 (rodent Taar1/human TAAR1) is a G protein-coupled receptor that is mainly recognized for its functions in neuromodulation. Previous in vitro studies suggested that Taar1 may signal from intracellular compartments. However, we have shown Taar1 to localize apically and on ciliary extensions in rodent thyrocytes, suggesting that at least in the thyroid, Taar1 may signal from the cilia at the apical plasma membrane domain of thyrocytes in situ, where it is exposed to the content of the follicle lumen containing putative Taar1 ligands. This study was designed to explore mouse Taar1 (mTaar1) trafficking, heterologously expressed in human and rat thyroid cell lines in order to establish an in vitro system in which Taar1 signaling from the cell surface can be studied in future. The results showed that chimeric mTaar1-EGFP traffics to the apical cell surface and localizes particularly to spherical structures of polarized thyroid cells, procilia, and primary cilia upon serum-starvation. Moreover, mTaar1-EGFP appears to form high molecular mass forms, possibly homodimers and tetramers, in stably expressing human thyroid cell lines. However, only monomeric mTaar1-EGFP was cell surface biotinylated in polarized human thyrocytes. In polarized rat thyrocytes, mTaar1-EGFP is retained in the endoplasmic reticulum, while cilia were reached by mTaar1-EGFP transiently co-expressed in combination with an HA-tagged construct of the related mTaar5. We conclude that Taar1 trafficking to cilia depends on their integrity. The results further suggest that an in vitro cell model was established that recapitulates Taar1 trafficking in thyrocytes in situ, in principle, and will enable studying Taar1 signaling in future, thus extending our general understanding of its potential significance for thyroid autoregulation.

scholarly journals Acrylamide does not induce tumorigenesis or major defects in mice in vivo

2008 ◽  
Vol 198 (2) ◽  
pp. 301-307 ◽  
Author(s):  
Ling Jin ◽  
Vanessa Chico-Galdo ◽  
Claude Massart ◽  
Christine Gervy ◽  
Viviane De Maertelaere ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Chronic Administration ◽  
Serum Levels ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Hormone Synthesis ◽  
Rat Thyroid

Chronic administration of acrylamide has been shown to induce thyroid tumors in rat. In vitro acrylamide also causes DNA damage, as demonstrated by the comet assay, in various types of cells including human thyroid cells and lymphocytes, as well as rat thyroid cell lines. In this work, mice were administered acrylamide in their drinking water in doses comparable with those used in rats, i.e., around 3–4 mg/kg per day for mice treated 2, 6, and 8 months. Some of the mice were also treated with thyroxine (T4) to depress the activity of the thyroid. Others were treated with methimazole that inhibits thyroid hormone synthesis and consequently secretion and thus induces TSH secretion and thyroid activation. These moderate treatments were shown to have their known effect on the thyroid (e.g. thyroid hormone and thyrotropin serum levels, thyroid gland morphology…). Besides, T4 induced an important polydipsia and degenerative hypertrophy of adrenal medulla. Acrylamide exerted various discrete effects and at high doses caused peripheral neuropathy, as demonstrated by hind-leg paralysis. However, it did not induce thyroid tumorigenesis. These results show that the thyroid tumorigenic effects of acrylamide are not observed in another rodent species, the mouse, and suggest the necessity of an epidemiological study in human to conclude on a public health policy.

scholarly journals Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 127 ◽  
Author(s):  
Michela Vitiello ◽  
Giuseppe Palma ◽  
Mario Monaco ◽  
Anna Bello ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Tumor Growth Rate ◽  
Stem Cell Markers ◽  
Thyroid Cells ◽  
Mesenchymal Transition ◽  
Rat Thyroid ◽  
The Impact ◽  
Thyroid Cancer Cells

PATZ1 is a transcriptional factor downregulated in thyroid cancer whose re-expression in thyroid cancer cells leads to a partial reversion of the malignant phenotype, including the capacity to proliferate, migrate, and undergo epithelial-to-mesenchymal transition. We have recently shown that PATZ1 is specifically downregulated downstream of the Ras oncogenic signaling through miR-29b, and that restoration of PATZ1 in Ha-Ras transformed FRTL5 rat thyroid cells is able to inhibit their capacities to proliferate and migrate in vitro. Here, we analyzed the impact of PATZ1 expression on the in vivo tumorigenesis of these cells. Surprisingly, FRTL5-Ras-PATZ1 cells showed enhanced tumor initiation when engrafted in nude mice, even if their tumor growth rate was reduced compared to that of FRTL5-Ras control cells. To further investigate the cause of the enhanced tumor engraftment of FRTL5-Ras-PATZ1 cells, we analyzed the stem-like potential of these cells through their capacity to grow as thyrospheres. The results showed that restoration of PATZ1 expression in these cells increases stem cell markers’ expression and self-renewal ability of the thyrospheres while limiting their growth capacity. Therefore, we suggest that PATZ1 may play a role in enhancing the stem cell potential of thyroid cancer cells, but, at the same time, it impairs the proliferation of non-stem cells.

scholarly journals microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

2014 ◽  
Vol 22 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Aparna Lakshmanan ◽  
Anna Wojcicka ◽  
Marta Kotlarek ◽  
Xiaoli Zhang ◽  
Krystian Jazdzewski ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Radioiodine Therapy ◽  
Expression Profiles ◽  
Hek293 Cells ◽  
Human Breast ◽  
Thyroid Cells ◽  
Promising Therapeutic Target ◽  
Rat Thyroid ◽  
Mcf 7

Na+/I−symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated.In silicoanalysis was used to identify miRs that may bind to the 3′UTR of humanNIS(hNIS). The top candidate miR-339-5p directly bound to the 3′UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels ofNISmRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropin-stimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38 miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3′UTR of hNISand its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased in most papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.

scholarly journals Rat Protein Tyrosine Phosphatase η Suppresses the Neoplastic Phenotype of Retrovirally Transformed Thyroid Cells through the Stabilization of p27Kip1

2000 ◽  
Vol 20 (24) ◽  
pp. 9236-9246 ◽  
Author(s):  
Francesco Trapasso ◽  
Rodolfo Iuliano ◽  
Angelo Boccia ◽  
Antonella Stella ◽  
Roberta Visconti ◽  
...  
Keyword(s):  
Map Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Protein Level ◽  
Tyrosine Phosphatase ◽  
Protein Stabilization ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Protein Tyrosine ◽  
Neoplastic Cell Transformation ◽  
Rat Thyroid

ABSTRACT The r-PTPη gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPη (the human homolog of r-PTPη) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPη gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Kioncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPη caused G1 growth arrest and increased the cyclin-dependent kinase inhibitor p27Kip1protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPη tumor suppressor activity is mediated by p27Kip1 protein stabilization, because suppression of p27Kip1 protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPη. Furthermore, we provide evidence that in v-mos-or v-ras-Ki-transformed thyroid cells, the p27Kip1 protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPη regulated p27Kip1 stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.

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