Interferon regulatory factor 3 mediates Poly(I:C)-induced innate immune response and apoptosis in non‑small cell lung cancer

Yi,Liang; Sun,Dan; Han,Qian; Liu,Zhonghui; Zeng,Zeng; Wu,Yanping; Chai,Xiaoyu; Liu,Xinmin

doi:10.3892/ijo.2018.4300

Interferon regulatory factor 3 mediates Poly(I:C)-induced innate immune response and apoptosis in non‑small cell lung cancer

Authors:
- Liang Yi
- Dan Sun
- Qian Han
- Zhonghui Liu
- Zeng Zeng
- Yanping Wu
- Xiaoyu Chai
- Xinmin Liu
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Affiliations: Department of Geriatrics, Peking University First Hospital, Beijing 100034, P.R. China
Published online on: March 5, 2018 https://doi.org/10.3892/ijo.2018.4300
Pages: 1623-1632

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Abstract

Immunotherapy is considered one of the most promising treatments for lung cancer. The cell signalling molecules melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I protein (RIG‑I) are essential receptors that recognise intracellular pathogen-associated nucleic acids, whereas interferon regulatory factor 3 (IRF3) controls the expression of innate immunity-associated genes in macrophages. However, the innate immune response to polyinosinic:polycytidylic acid [Poly(I:C)] in lung cancer remains to be elucidated. In the present study, western blot analysis, reverse transcription-quantitative polymerase chain reaction, RNA interference, IRF3 plasmid construction, ELISA and apoptosis analysis were employed to study the innate immune response and apoptosis of non‑small cell lung cancer (NSCLC) cells. Poly(I:C) transfection in NSCLC cells triggered apoptosis via the extrinsic apoptotic pathway, and activated the innate immune response by promoting interferon-β and C-X-C motif chemokine ligand 10 expression. Treatment with the IκB kinase ε/tumour necrosis factor receptor-associated factor family member-associated nuclear factor-κB activator-binding kinase 1 inhibitor BX795, which inhibits IRF3 phosphorylation, or transfection with small interfering RNA/short hairpin RNA to downregulate MDA5, RIG‑I or IRF3, prior to Poly(I:C) transfection inhibited the innate immune response and apoptotic pathway. Conversely, IRF3 overexpression promoted activation of the apoptotic pathway, thus indicating that the MDA5/RIG‑I/IRF3 axis may mediate responses to Poly(I:C) transfection. Furthermore, phosphorylation of the transcription factor signal transducer and activator of transcription 1 (STAT1) was associated with the alterations in IRF3 phosphorylation and apoptosis, thus suggesting that STAT1 may be involved in Poly(I:C)-induced apoptosis. In NSCLC surgical samples, MDA5, RIG‑I and IRF3 were highly expressed, whereas the expression levels of phosphorylated‑IRF3 were reduced. These findings indicated that the function of the MDA5/RIG‑I/IRF3 axis may be impaired in some lung cancers. In conclusion, the present findings suggested that the MDA5/RIG‑I/IRF3 axis, which is associated with innate immunity, is intact in NSCLC cells, and IRF3 is involved in regulating the apoptotic pathway in NSCLC cells.

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