Abstract Nuclear epithelial growth factor receptor (EGFR) plays an important role in the development, metastasis, treatment, and prognosis of cancer. Radiotherapy, one of the main therapies for malignant tumor, causes EGFR transfer into the nucleus along with tumor therapy, thereby reducing radiosensitivity. Insight into the biological characteristics and functions of nuclear EGFR has an important reference value for improving radiosensitivity. Therefore, this article elaborates on EGFR transport into the nucleus, the features of nuclear EGFR, and its relationship with radiosensitivity and clinical targeted therapy.
Fund:National Natural Science Foundation of China (31600679); Project of Science and Technology Department of Jilin Province (20090458); Project of Health and Family Planning Commission of Jilin Province (2014ZC054);Bethune Special Research of Science and Technology Department of Jilin Province (20160101079JC); Horizontal Project of Jilin University (2015373)
[1] Bossi P,Resteghini C,Paielli N,et al. Prognostic and predictive value of EGFR in head and neck squamous cell carcinoma[J].Oncotarget,2016,7(45):74362-74379.DOI:10.18632/oncotarget.11413 [2] Raymond E,Faivre S,Armand JP,et al. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy[J].Drugs,2000,60 Suppl 1:15-23;41-42 [3] Cuneo KC,Nyati MK,Ray D,et al. EGFR targeted therapies and radiation:Optimizing efficacy by appropriate drug scheduling and patient selection[J].Pharmacol Ther,2015,154:67-77.DOI:10.1016/j.pharmthera.2015.07.002 [4] Brand TM,Iida M,Li C,et al. The Nuclear Epidermal Growth Factor Receptor Signaling Network and its Role in Cancer[J].Discov Med,2011,12(66):419-432 [5] Lo HW,Xia W,Wei Y,et al. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer[J].Cancer Res,2005,65(1):338-348 [6] Marti U, Burwen SJ,Wells A,et al. Localization of epidermal growth factor receptor in hepatocyte nuclei[J].Hepatology,1991,13(1):15-20 [7] Psyrri A,Yu Z,Weinberger PM,et al. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis[J].Clin Cancer Res,2005,11(16):5856-62.DOI:10.1158/1078-0432.CCR-05-0420 [8] Dittmann K,Mayer C,Kehlbach,et al. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK[J].Mol Cancer,2008,7:69.DOI:10.1186/1476-4598-7-69 [9] Dittmann K,Mayer C,Fehrenbacher B,et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase[J].J Biol Chem,2005,280(35):31182-31189.DOI:10.1074/jbc. M506591200 [10] De Angelis Campos AC,Rodrigues MA,de Andrade C,et al. Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway[J].Biochem Biophys Res Commun,2011,412(2):341-346.DOI:10.1016/j.bbrc.2011.07.100 [11] Lo HW,Hung MC.Nuclear EGFR signalling network in cancers:linking EGFR pathway to cell cycle progression,nitric oxide pathway and patient survival[J].Br J Cancer,2006,94(2):184-188.DOI:10.1038/sj.bjc.6602941 [12] Lo HW,Ali-Seyed M,Wu Y,et al. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis,importin beta1 and CRM1[J].J Cell Biochem,2006,98(6):1570-1583.DOI:10.1002/jcb.20876 [13] Liao HJ,Carpenter G.Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol Biol Cell,2007,18(3):1064-1072.DOI:10.1091/mbc. E06-09-0802 [14] Wang YN,Yamaguchi H,Huo L,et al. The translocon Sec61beta localized in the inner nuclear membrane transports membrane-embedded EGF receptor to the nucleus[J].J Biol Chem,2010,285(49):38720-38729.DOI:10.1074/jbc. M110.158659 [15] Wanner G,Mayer C,Kehlbach R,et al. Activation of protein kinase Cepsilon stimulates DNA-repair via epidermal growth factor receptor nuclear accumulation[J].Radiother Oncol,2008,86(3):383-390.DOI:10.1016/j.radonc.2007.10.041 [16] Liccardi G,Hartley JA,Hochhauser D.EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment[J].Cancer Res,2011,71(3):1103-1114.DOI:10.1158/0008-5472.CAN-10-2384 [17] Yu YL,Chou RH,Wu CH,et al. Nuclear EGFR suppresses ribonuclease activity of polynucleotide phosphorylase through DNAPK-mediated phosphorylation at serine 776[J].J Biol Chem,2012,287(37):31015-31026.DOI:10.1074/jbc. M112.358077 [18] Dittmann K,Mayer C,Fehrenbacher B,et al. Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654[J].FEBS Lett,2010,584(18):3878-84.DOI:10.1016/j.febslet.2010.08.005 [19] Dittmann K,Mayer C,Wanner G,et al. The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor-and DNA-dependent kinase phosphorylation[J].Radiother Oncol,2007,84(3):328-34.DOI:10.1016/j.radonc.2007.07.006 [20] Dittmann K,Mayer C,Fehrenbacher B,et al. Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access[J].Radiother Oncol,2011,99(3):317-322.DOI:10.1016/j.radonc.2011.06.001 [21] Graddzka I,Sochanowicz B,Brzóska K,et al. Cis-9,trans-11-conjugated linoleic acid affects lipid raft composition and sensitizes human colorectal adenocarcinoma HT-29 cells to X-radiation[J].Biochim Biophys Acta,2013,1830(1):2233-2242.DOI:10.1016/j.bbagen.2012.10.015 [22] Lin SY,Makino K,Xia W,et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor[J].Nat Cell Biol,2001,3(9):802-808 [23] Brand TM,Iida M,Li C,et al. The nuclear epidermal growth factor receptor signaling network and its role in cancer[J].Discov Med,2011,12(66):419-432 [24] Henrich SM,Usadel C,Werwein E,et al. Interplay with the Mre11-Rad50-Nbs1 complex and phosphorylation by GSK3beta implicate human B-Myb in DNA-damage signaling[J].Sci Rep,2017.7:41663.DOI:10.1038/srep41663 [25] Joaquin M,Watson RJ.Cell cycle regulation by the B-Myb transcription factor[J].Cell Mol Life Sci,2003,60(11):2389-2401.DOI:10.1007/s00018-003-3037-4 [26] Diehl JA.Cycling to cancer with cyclin D1[J].Cancer Biol Ther,2002,1(3):226-231 [27] Xia W,Wei Y,Du Y,et al. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer[J].Mol Carcinog,2009,48(7):610-617.DOI:10.1002/mc.20504 [28] Bitler BG,Goverdhan A,Schroeder JA.MUC1 regulates nuclear localization and function of the epidermal growth factor receptor[J].J Cell Sci,2010,123(Pt 10):1716-1723.DOI:10.1242/jcs.062661 [29] Huo L,Wang YN,Xia W,et al. RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus[J].Proc Natl Acad Sci USA,2010.107(37):16125-16130.DOI:10.1073/pnas.1000743107 [30] Lo HW,Cao X,Zhu H,et al. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvⅢ-STAT3 signaling axes[J].Mol Cancer Res,2010,8(2):232-245.DOI:10.1158/1541-7786.MCR-09-0391 [31] Lo HW,Hsu SC,Ali-Seyed M,et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway[J].Cancer Cell,2005,7(6):575-89.DOI:10.1016/j.ccr.2005.05.007 [32] Jaganathan S,Yue P,Paladino DC,et al. A functional nuclear epidermal growth factor receptor,SRC and Stat3 heteromeric complex in pancreatic cancer cells[J/OL].PLoS One,2011,6(5):e19605.DOI:10.1371/journal.pone.0019605 [33] Chua CY,Liu Y,Granberg KJ,et al. IGFBP2 potentiates nuclear EGFR-STAT3 signaling[J].Oncogene,2016,35(6):738-747.DOI:10.1038/onc.2015.131 [34] Stoimenov I,Helleday T.PCNA on the crossroad of cancer[J].Biochem Soc Trans,2009.37(Pt 3):605-13.DOI:10.1042/BST0370605 [35] Wang SC,Nakajima Y,Yu YL,et al. Tyrosine phosphorylation controls PCNA function through protein stability[J].Nat Cell Biol,2006,8(12):1359-1368.DOI:10.1038/ncb1501 [36] Tong D,Ortega J,Kim C,et al. Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA phosphorylation[J].J Biol Chem,2015,290(23):14536-14541.DOI:10.1074/jbc. M115.641399 [37] Yu YL,Chou RH,Liang JH,et al. Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides[J/OL].PLoS One,2013.8(4):e61362.DOI:10.1371/journal.pone.0061362 [38] Toulany M,Minjgee M,Kehlbach R,et al. ErbB2 expression through heterodimerization with erbB1 is necessary for ionizing radiation-but not EGF-induced activation of Akt survival pathway[J].Radiother Oncol,2010,97(2):338-345.DOI:10.1016/j.radonc.2010.03.008 [39] Maier P,Hartmann L,Wenz F,et al. Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization[J].Int J Mol Sci,2016,17(1):102.DOI:10.3390/ijms17010102 [40] Paglin S,Lee NY,Nakar C,et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential,autophagy,and survival in irradiated MCF-7 cells[J].Cancer Res,2005,65(23):11061-70.DOI:10.1158/0008-5472.CAN-05-1083 [41] Brand TM,Iida M,Dunn EF,et al. Nuclear epidermal growth factor receptor is a functional molecular target in triple-negative breast cancer[J].Mol Cancer Ther,2014,13(5):1356-1368.DOI:10.1158/1535-7163.MCT-13-1021 [42] Wang C,Fu X,Cai X,et al. High-dose nimotuzumab improves the survival rate of esophageal cancer patients who underwent radiotherapy[J].Onco Targets Ther,2016,9:117-122.DOI:10.2147/OTT.S89592 [43] Teng K,Zhang Y,Hu X,et al. Nimotuzumab enhances radiation sensitivity of NSCLC H292 cells in vitro by blocking epidermal growth factor receptor nuclear translocation and inhibiting radiation-induced DNA damage repair[J].Onco Targets Ther,2015,8:809-18.DOI:10.2147/OTT.S77283