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Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer

Oncogene volume 31, pages 2555–2565 (2012)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by grants from the National Health Research Institutes (99A1-EOPP02-014) and the National Science Council (NSC 97-2320-B-040-016 and NSC 97-2314-B-400-010) of Taiwan.

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  1. J T Chang and P Lin: These authors contributed equally to this work.

  2. School of Medicine, China Medical University, Taichung, Taiwan

Authors and Affiliations

  1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

    P-H Chen, J T Chang & P Lin

  2. Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan

    P-H Chen, J T Chang & P Lin

  3. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan

    P-H Chen

  4. Department of Pathology, China Medical University Hospital, Taichung, Taiwan

    H Chang

  5. Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

    J T Chang

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Chen, PH., Chang, H., Chang, J. et al. Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer. Oncogene 31, 2555–2565 (2012). https://doi.org/10.1038/onc.2011.438

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