title: KIT Exon 11 Codons 557-558 Deletion Mutation Promotes Liver Metastasis Through the CXCL12/CXCR4 Axis in Gastrointestinal Stromal Tumors.
abstract: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.
  
  
  
  A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.
  
  
  
  Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT Δ557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557-558-mediated cell migration. Moreover, KIT Δ557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Δ557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.
  
  
  
  KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477-87. ©2016 AACR.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hao-Chen
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Li
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Ying-Jui
authors.initials: YJ
authors.lastname: Chao
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Hou
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Yuan-Shuo
authors.initials: YS
authors.lastname: Hsueh
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Surgery, Tainan Hospital, Department of Health, Executive Yuan, Tainan, Taiwan. ysshan@mail.ncku.edu.tw kc520.ee22@msa.hinet.net.
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan. ysshan@mail.ncku.edu.tw kc520.ee22@msa.hinet.net.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Shan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics*; D003062:Codon / Q000235:genetics; D005091:Exons / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D003062:Codon; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit