title: Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms.
  
  
  METHODS
  Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model.
  
  
  RESULTS
  Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue.
  
  
  CONCLUSIONS
  Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.
authors.affiliation: Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, No 651 Dongfeng Road East, Guangzhou 510060, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: He
authors.forename: Mian
authors.initials: M
authors.lastname: Xi
authors.forename: Mu-Yan
authors.initials: MY
authors.lastname: Cai
authors.forename: Jing-Xian
authors.initials: JX
authors.lastname: Shen
authors.forename: Qiao-Qiao
authors.initials: QQ
authors.lastname: Li
authors.forename: Yi-Ji
authors.initials: YJ
authors.lastname: Liao
authors.forename: Dong
authors.initials: D
authors.lastname: Qian
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Feng
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Meng-Zhong
authors.initials: MZ
authors.lastname: Liu
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D011836:Radiation Tolerance; D015854:Up-Regulation
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C501466:nimotuzumab; D066246:ErbB Receptors