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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.

Author information

Cui YH1, Suh Y1, Lee HJ2, Yoo KC1, Uddin N1, Jeong YJ2, Lee JS3, Hwang SG4, Nam SY5, Kim MJ6, Lee SJ1.

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

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

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

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

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

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