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Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor

Oncogene volume 34, pages 5372–5382 (2015)Cite this article

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Abstract

Despite ionizing radiation (IR) is being widely used as a standard treatment for lung cancer, many evidences suggest that IR paradoxically promotes cancer malignancy. However, its molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that exposure to fractionated radiation (2 Gy per day for 3 days) induces the secretion of granulocyte-colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. Intriguingly, radiation-induced G-CSF promoted the migratory and invasive properties by triggering the epithelial–mesenchymal cell transition (EMT) in non-small-cell lung cancer cells (NSCLCs). By irradiation, G-CSF was upregulated transcriptionally by β-catenin/TCF4 complex that binds to the promoter region of G-CSF as a transcription factor. Importantly, irradiation increased the stability of β-catenin through the activation of PI3K/AKT (phosphatidylinositol 3-kinase/AKT), thereby upregulating the expression of G-CSF. Radiation-induced G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3 (Janus kinase/signal transducers and activators of transcription), thereby triggering EMT program in NSCLCs. Taken together, our findings suggest that the application of G-CSF in cancer therapies to ameliorate neutropenia should be reconsidered owing to its effect on cancer progression, and G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy for the treatment of NSCLC.

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Abbreviations

G-CSF:

granulocyte colony-stimulating factor

IR:

ionizing radiation

NSCLC:

non-small-cell lung cancer

EMT:

epithelial–mesenchymal cell transition

siRNA:

small interfering RNA.

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Acknowledgements

This work was supported by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean Government, through its National Nuclear Technology Program (2012M2A2A7035878), and the Ministry of Trade, Industry and Energy (Grant No: 20131610101840).

Author Contributions

Y-HC: conception and design, collection and assembly of data, data analysis and interpretation; YS: conception and design, data analysis and interpretation, manuscript writing; H-JL: data analysis and interpretation; K-CY: data analysis and interpretation; NU: data analysis and interpretation; Y-JJ: data analysis and interpretation; J-SL: data analysis and interpretation; S-GH: data analysis and interpretation; S-YN: data analysis and interpretation; M-JK: conception and design, collection and assembly of data, data analysis and interpretation; S-JL: conception and design, data analysis and interpretation, financial support, final approval of manuscript.

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Author notes

  1. Y-H Cui and Y Suh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Life Science, Laboratory of Molecular Biochemisty, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea

    Y-H Cui, Y Suh, K-C Yoo, N Uddin & S-J Lee

  2. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    H-J Lee & Y-J Jeong

  3. Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, Korea

    J-S Lee

  4. Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    S-G Hwang

  5. Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul, Korea

    S-Y Nam

  6. Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    M-J Kim

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Cui, YH., Suh, Y., Lee, HJ. et al. Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor. Oncogene 34, 5372–5382 (2015). https://doi.org/10.1038/onc.2014.466

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  • DOI: https://doi.org/10.1038/onc.2014.466

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