Abstract
Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis.
Highlights
The Aryl hydrocarbon Receptor (AhR) is a cytosolic ligand-activated transcription factor, originally characterized as an important player of detoxification pathways for xenobiotics and environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs)
Aryl hydrocarbon receptor (AhR) expression was evaluated by quantitative polymerase chain reaction in 90 papillary thyroid cancers (PTCs), 11 medullary thyroid cancers (MTCs), and 6 anaplastic thyroid cancers (ATCs) and by immunohistochemistry (IHC) in a subgroup of 41 of the 90 PTCs
We evaluated AhR expression in thyroid cancer samples derived from transgenic mice characterized by conditional expression of BRAFV600E in the thyroid
Summary
The Aryl hydrocarbon Receptor (AhR) is a cytosolic ligand-activated transcription factor, originally characterized as an important player of detoxification pathways for xenobiotics and environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs). More than 400 exogenous ligands have been identified including 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), the most powerful AhR agonist [1]. As a result of ligand binding, AhR dissociates from a chaperone complex The AhR/ARNT complex binds xenobiotic or dioxin-responsive elements (XRE or DRE) regions, which are enhancer DNA elements located in the 50 -flanking region. Cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) are almost totally dependent on AhR activity and are implicated in detoxification of xenobiotics. AhR is highly conserved across different species [2] and constitutively expressed practically in all tissue, especially placenta, liver and lungs
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