The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition
The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition
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DOI：
10.3390/cancers12010145
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发表时间：
2020-01-01
期刊：
影响因子：
5.2
通讯作者：
Puxeddu, Efisio
中科院分区：
文献类型：
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作者：
Moretti, Sonia;Nucci, Nicole;Puxeddu, Efisio
芳香烃受体（Aryl hydrocarbon receptor，AhR）是一种重要的肿瘤细胞受体，它参与肿瘤细胞的发生、发展和侵袭，调节肿瘤细胞的增殖、分化、基因表达、炎症反应、细胞运动和迁移等。此外，AhR的免疫抑制功能已被认识到。本研究评估了AhR表达及其在甲状腺癌进展中的作用。在107个甲状腺癌样本（90个PTC，11个MTC，6个ATC）中通过qPCR评估AhR表达，并在41个PTC中通过免疫组织化学评估AhR表达。为了估计受体活化，测量靶基因CYP 1A 1和CYP 1B 1的表达。通过分析参与EMT和细胞运动的基因的表达，在犬尿氨酸刺激的FTC-133和BcPap细胞系中评价AhR功能效应。与正常甲状腺相比，所有分析的甲状腺癌样本中AhR mRNA表达均显著升高，并检测到与CYP 1B 1的统计学显著相关性。犬尿氨酸刺激的FTC-133和BcPap显示出特定AhR驱动的EMT程序的激活，其特征在于E-钙粘蛋白减少和SLUG、N-钙粘蛋白和纤连蛋白增加，导致细胞运动和侵袭的增强。这项研究证实了IDO 1-Kyn-AhR通路在甲状腺癌肿瘤发生中的重要性，表明AhR在介导免疫抑制微环境中起关键作用，并有利于获得可促进侵袭和转移的间充质表型。
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.