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IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model

Oncogene volume 36, pages 6315–6324 (2017)Cite this article

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Abstract

The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop ‘NRF2 addiction.’ Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers.

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Acknowledgements

We thank Dr Keiko Nakayama for providing a mutant HRAS-expression vector, pMX-puro-HRASG12V, Drs. Norio Suzuki and Masayuki Yamamoto for providing SV40 T antigen expressing vectors, HA-KEAP1 cDNA and intensive discussion, and Drs Tomohiro Nakamura and Atsushi Hozawa for checking the quality of quantitative data and the adequacy of their presentation. We also thank Ms Nao Ohta for technical assistance and the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support. This work was supported by JSPS KAKENHI Grant Numbers JP26860180 (HK), 15H04692 (HM) and 16K15228 (HM), Daiichi Sankyo Foundation of Life Science (HM), the Uehara Memorial Foundation (HM), the Mitsubishi Foundation (HM), the Naito Foundation (HM), and the Princess Takamatsu Cancer Research Fund 15-24728 (HM). The funders had no role in the design of the study, data collection and analysis, decision to publish or preparation of the manuscript.

Author contributions

HK designed the research, conducted the experiments using cell lines and mice, and wrote early drafts of the manuscript. YO and TS conducted analysis of the human breast cancer cases. SM helped with the in vivo tumorigenesis experiments. HM designed the research, analyzed the data, and wrote the manuscript.

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Authors and Affiliations

  1. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    H Kitamura, S Murakami & H Motohashi

  2. Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Y Onodera

  3. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan

    T Suzuki

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  1. H Kitamura
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Correspondence to H Motohashi.

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Kitamura, H., Onodera, Y., Murakami, S. et al. IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. Oncogene 36, 6315–6324 (2017). https://doi.org/10.1038/onc.2017.236

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