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Interferon-γ induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors

Oncogene volume 25, pages 3670–3679 (2006)Cite this article

Abstract

We have developed an epithelial cell carcinoma model for studying efficacy of IFNγ gene therapy and have identified components of IFNγ-signaling pathway responsible for its direct anti-tumor actions. The tumor results from ectopic expression of SV40 Large T-Antigen (SV40 T-Ag) oncogene in lens of transgenic mouse (αT3) and complete regression of the tumor is induced by targeting expression of IFNγ into malignant lens cells. Inflammatory cells are absent in lens of αT3 or DT (co-expressing IFNγ and SV40-T-Antigen) mice and the transformed lens cells are non-immunogenic, suggesting non-involvement of immunologic cells. We show that IFNγ has direct growth-inhibitory effects on tumor cells, induces death of tumor cells by apoptosis and that these effects are mediated by two transcription factors, IRF-1 (interferon-regulatory factor-1) and ICSBP (interferon-consensus sequence-binding protein) induced by IFNγ. Furthermore, stable transfection with ICSBP or IRF-1 construct inhibits lens carcinoma cell growth by upregulating Caspase-1, p21WAF1 and p27 expression. In contrast, tumor progression in αT3 lens correlates with inhibition of IRF-1 and ICSBP expression. Our results suggest that IFNγ gene therapy maybe effective in malignant diseases for which DNA tumor viruses are etiologic agents and that antitumor actions of IRF-1/ICSBP can be exploited therapeutically to circumvent adverse clinical effects associated with IFN therapy.

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Acknowledgements

We thank Dr Michele K Evans, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825 for careful reading of the manuscript.

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Authors and Affiliations

  1. Laboratories of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    C E Egwuagu, W Li, C-R Yu, M Che Mei Lin & C-C Chan

  2. Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, Toyama, Japan

    T Nakamura

  3. Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    A B Chepelinsky

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  1. C E Egwuagu
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Correspondence to C E Egwuagu.

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Egwuagu, C., Li, W., Yu, CR. et al. Interferon-γ induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors. Oncogene 25, 3670–3679 (2006). https://doi.org/10.1038/sj.onc.1209402

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