The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines.
The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines.
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DOI：
10.1002/mc.22032
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发表时间：
2014-10
影响因子：
4.6
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
--
作者：
John, Kaarthik;Lahoti, Tejas S.;Wagner, Kelly;Hughes, Jarod M.;Perdew, Gary H.
先前在头颈部鳞状细胞癌（HNSCC）细胞系中的研究已经揭示，Ah受体（AHR）在介导这些细胞的“侵袭性”表型中起重要作用，所述表型包括增强的炎症信号传导（例如IL 6）和迁移潜力。在这里，我们试图确定与增强肿瘤侵袭性相关的AHR的推定新靶点。全局基因表达分析鉴定了在用AHR拮抗剂处理OSC-19或HN 30细胞后被抑制的许多基因。三种生长因子是AHR活性的靶点;双调蛋白（AREG）、表皮调节蛋白（EREG）和血小板衍生生长因子A（PDGFA）被AHR拮抗剂抑制并进一步检查。定量PCR分析，ELISA和siRNA介导的敲低AHR揭示了衰减的基础和/或诱导水平的这些生长因子的表达在两个HNSCC线，以下AHR拮抗作用。计算机模拟分析表明，这些生长因子具有二恶英样反应元件。另外两种AHR配体6-甲酰吲哚并[3，2-B]咔唑和苯并（a）芘也引起类似的反应。总之，本研究确定AREG、EREG和PDGFA为与HNSCC细胞转移表型相关的AHR活性的生长因子靶标，表明减弱AHR活性可能是一种治疗策略。
Previous studies in head and neck squamous cell carcinoma (HNSCC) cell lines have revealed that the Ah receptor (AHR) plays a significant role in mediating the ‘aggressive’ phenotype of these cells, which includes enhanced inflammatory signaling (e.g. IL6) and migratory potential. Here we sought to identify putative novel targets of the AHR associated with enhanced tumor invasiveness. Global gene expression analysis identified a number of genes that are repressed upon treatment of OSC-19 or HN30 cells with an AHR antagonist. Three growth factors were targets of AHR activity; amphiregulin (AREG), epiregulin (EREG) and platelet-derived growth factor A (PDGFA) were repressed by an AHR antagonist and further examined. Quantitative PCR analysis, ELISA and siRNA-mediated knock down of AHR revealed an attenuation of basal and/or induced levels of expression of these growth factors in two HNSCC lines, following AHR antagonism. In silico analysis revealed that these growth factors possess dioxin-like response elements. Two other AHR ligands, 6-formylindolo[3,2-b]carbazole and benzo(a)pyrene also elicited similar responses. In conclusion, this study identified AREG, EREG and PDGFA as growth factor targets of AHR activity associated with metastatic phenotype of HNSCC cells, suggesting that attenuation of AHR activity may be a therapeutic strategy.
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