title: Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor.
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.
authors: Laboratory of Molecular Biochemisty, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors: Y-H
authors: YH
authors: Cui
authors: Laboratory of Molecular Biochemisty, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors: Y
authors: Y
authors: Suh
authors: Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors: H-J
authors: HJ
authors: Lee
authors: Laboratory of Molecular Biochemisty, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors: K-C
authors: KC
authors: Yoo
authors: Laboratory of Molecular Biochemisty, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors: N
authors: N
authors: Uddin
authors: Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors: Y-J
authors: YJ
authors: Jeong
authors: Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, Korea.
authors: J-S
authors: JS
authors: Lee
authors: Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors: S-G
authors: SG
authors: Hwang
authors: Radiation Health Institute, Korea Hydro and Nuclear Power Co. Ltd, Seoul, Korea.
authors: S-Y
authors: SY
authors: Nam
authors: Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors: M-J
authors: MJ
authors: Kim
authors: Laboratory of Molecular Biochemisty, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors: S-J
authors: SJ
authors: Lee
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019583:Dose Fractionation, Radiation; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006801:Humans; D053613:Janus Kinase 1 / Q000502:physiology; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D051057:Proto-Oncogene Proteins c-akt
references: Int J Mol Med. 2006 Aug;18(2):365-73
references: 16820947
references: Int J Cancer. 2004 May 10;109(6):826-32
references: 15027115
references: Cancer Cell. 2014 May 12;25(5):605-20
references: 24823638
references: Neural Dev. 2013 Apr 25;8:7
references: 23618343
references: Int J Cancer. 1994 Feb 1;56(3):446-51
references: 8314333
references: J Neurosci. 2009 Sep 16;29(37):11572-81
references: 19759304
references: J Infect Dis. 1995 Oct;172(4):1061-75
references: 7561181
references: Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19204-9
references: 22080605
references: J Biol Chem. 2007 Apr 13;282(15):11221-9
references: 17287208
references: Blood. 1991 Dec 1;78(11):2791-808
references: 1720034
references: Oncol Rep. 2007 Apr;17(4):955-61
references: 17342342
references: Int J Oncol. 2013 May;42(5):1801-6
references: 23483258
references: Nat Med. 2007 Jan;13(1):62-9
references: 17159986
references: Int J Oncol. 2014 May;44(5):1643-51
references: 24573038
references: Blood. 1980 Dec;56(6):947-58
references: 7002232
references: Nihon Kyobu Shikkan Gakkai Zasshi. 1992 Jul;30(7):1327-32
references: 1383587
references: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21248-55
references: 21081700
references: Front Oncol. 2012 Jun 04;2:58
references: 22675673
references: JAKSTAT. 2014 Jan 1;3(1):e28975
references: 24843831
references: Curr Drug Targets. 2010 Jun;11(6):745-51
references: 20041844
references: J Clin Invest. 2014 Apr;124(4):1853-67
references: 24642471
references: J Cell Biochem. 2011 Jun;112(6):1544-51
references: 21344483
references: Mol Diagn Ther. 2011 Dec 1;15(6):347-52
references: 22208386
references: Trends Cell Biol. 2012 Apr;22(4):211-9
references: 22245068
references: J Clin Invest. 2004 Aug;114(4):569-81
references: 15314694
references: Cancer Cell. 2010 Dec 14;18(6):619-29
references: 21156285
references: Nat Rev Cancer. 2004 Sep;4(9):737-47
references: 15343280
references: PLoS One. 2012;7(2):e30820
references: 22319590
references: Growth Factors. 1996;13(3-4):251-60
references: 8919032
references: Pol Arch Med Wewn. 2000 Mar-Apr;103(3-4):163-8
references: 11236243
references: J Clin Oncol. 2008 Jun 10;26(17):2916-24
references: 18539973
references: Lab Invest. 2014 Apr;94(4):362-70
references: 24468793
references: Nat Rev Cancer. 2009 May;9(5):351-60
references: 19377507
references: Clin Chem Lab Med. 2004;42(12):1347-54
references: 15576295
references: J Cell Biochem. 2008 Apr 1;103(5):1512-23
references: 17879956
references: Oncol Rep. 2012 Jan;27(1):51-7
references: 21971767
references: Science. 1985 Jul 5;229(4708):16-22
references: 2990035
references: Cancer Cell. 2012 Jun 12;21(6):836-47
references: 22698407
references: Int J Urol. 2007 Nov;14 (11):1034-9
references: 17956532
references: Endocr Relat Cancer. 1999 Mar;6(1):41-4
references: 10732785
references: Cell. 2012 Jun 8;149(6):1192-205
references: 22682243
references: Jpn J Clin Oncol. 1998 Sep;28(9):559-62
references: 9793030