Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
Mol Cancer Res. 2012 Oct;10(10):1369-79. doi: 10.1158/1541-7786.MCR-12-0216. Epub 2012 Aug 21.
The aryl hydrocarbon receptor (AhR) has been shown to play a role in an increasing number of cellular processes. Recent reports have linked the AhR to cell proliferation, cytoskeletal arrangement, and tumor invasiveness in various tumor cell types. The AhR plays a role in the de-repression of the interleukin (IL)6 promoter in certain tumor cell lines, allowing for increased transcriptional activation by cytokines. Here, we show that there is a significant level of constitutive activation of the AhR in cells isolated from patients with head and neck squamous cell carcinoma (HNSCC). Constitutive activation of the AhR in HNSCCs was blocked by antagonist treatment, leading to a reduction in IL6 expression. In addition, the AhR exhibits a high level of expression in HNSCCs than in normal keratinocytes. These findings led to the hypothesis that the basal AhR activity in HNSCCs plays a role in the aggressive phenotype of these tumors and that antagonist treatment could mitigate this phenotype. This study provides evidence that antagonism of the AhR in HNSCC tumor cells, in the absence of exogenous receptor ligands, has a significant effect on tumor cell phenotype. Treatment of these cell lines with the AhR antagonists 6, 2', 4'-trimethoxyflavone, or the more potent GNF351, decreased migration and invasion of HNSCC cells and prevented benzo[a]pyrene-mediated induction of the chemotherapy efflux protein ABCG2. Thus, an AhR antagonist treatment has been shown to have therapeutic potential in HNSCCs through a reduction in aggressive cell phenotype.
芳香烃受体 (AhR) 在越来越多的细胞过程中发挥作用已得到证实。最近的报告将 AhR 与各种肿瘤细胞类型中的细胞增殖、细胞骨架排列和肿瘤侵袭联系起来。AhR 在某些肿瘤细胞系中白细胞介素 (IL)6 启动子的去抑制中起作用，允许细胞因子增加转录激活。在这里，我们表明，从头颈部鳞状细胞癌 (HNSCC) 患者分离的细胞中存在 AhR 的显著水平的组成型激活。AhR 在 HNSCC 中的组成型激活被拮抗剂治疗阻断，导致 IL6 表达减少。此外，AhR 在 HNSCC 中的表达水平高于正常角质形成细胞。这些发现导致假设 HNSCC 中的基础 AhR 活性在这些肿瘤的侵袭表型中起作用，并且拮抗剂治疗可以减轻这种表型。这项研究提供了证据，表明在没有外源性受体配体的情况下，拮抗 HNSCC 肿瘤细胞中的 AhR 对肿瘤细胞表型有显著影响。用 AhR 拮抗剂 6、2'、4'-三甲氧基黄酮或更有效的 GNF351 处理这些细胞系，可减少 HNSCC 细胞的迁移和侵袭，并防止苯并[a]芘介导的化疗外排蛋白 ABCG2 的诱导。因此，通过减少侵袭性细胞表型，AhR 拮抗剂治疗已显示出在 HNSCC 中的治疗潜力。
