Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Oncogene. 2012 May 17;31(20):2555-65. doi: 10.1038/onc.2011.438. Epub 2011 Sep 26.
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by cigarette smoke. Previously, we demonstrated that AhR is overexpressed in lung adenocarcinomas (ADs). In this study we observed that AhR expression is significantly correlated with nuclear RelA (a nuclear factor-κB (NFκB) subunit) and cytosolic interleukin-6 (IL-6) in 200 non-small cell lung cancer patients, especially among never smokers. Overexpression of AhR increased IL-6 expression in H1355 cells and immortalized human bronchial epithelial cells BEAS-2B. As NFκB inhibitor and knockdown RelA expression greatly reduced constitutive AhR-induced IL-6 expression, we hypothesized that AhR expression, in the absence of exogenous ligand, is able to modulate NFκB activity and subsequently upregulate IL-6 expression, thus promoting the development of lung AD. Specifically, AhR overexpression significantly increased NFκB activity, whereas interference with AhR expression significantly reduced NFκB activity and IL-6 expression in H1355 cells. We demonstrated that AhR associates with RelA in the cytosol and nucleus of human lung cells. Furthermore, AhR overexpression enhanced nuclear localization of AhR and RelA, and increased the association of AhR-RelA with the NFκB response element of the IL-6 promoter. However, p50 was not involved. Our results indicate that AhR, without exposure to a ligand, associates with RelA, which then positively modulates NFκB activity and then upregulates IL-6 expression in human lung cells. Thus we have identified a new mechanism for lung tumorigenesis in non-smokers.
芳香烃受体 (AhR) 是一种配体激活的转录因子,可被香烟烟雾激活。此前,我们证明 AhR 在肺腺癌 (AD) 中过表达。在这项研究中,我们观察到 200 名非小细胞肺癌患者中 AhR 表达与核 RelA(核因子-κB (NFκB) 亚基)和细胞质白细胞介素-6 (IL-6) 显著相关,尤其是从不吸烟者。AhR 的过表达增加了 H1355 细胞和永生化人支气管上皮细胞 BEAS-2B 中的 IL-6 表达。由于 NFκB 抑制剂和 RelA 表达的敲低大大降低了组成型 AhR 诱导的 IL-6 表达,我们假设 AhR 表达在没有外源性配体的情况下能够调节 NFκB 活性,随后上调 IL-6 表达,从而促进肺 AD 的发展。具体而言,AhR 过表达显著增加了 NFκB 活性,而干扰 AhR 表达则显著降低了 H1355 细胞中的 NFκB 活性和 IL-6 表达。我们证明 AhR 在人肺细胞的细胞质和细胞核中与 RelA 结合。此外,AhR 过表达增强了 AhR 和 RelA 的核定位,并增加了 AhR-RelA 与 IL-6 启动子 NFκB 反应元件的结合。然而,p50 并未参与其中。我们的结果表明,AhR 在没有暴露于配体的情况下与 RelA 结合,然后正向调节 NFκB 活性,然后在上调人肺细胞中的 IL-6 表达。因此,我们已经确定了非吸烟者肺癌发生的一种新机制。