title: Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling.
abstract: BACKGROUND
  Administration of trastuzumab, a fully humanized monoclonal antibody targeted to the human epidermal growth factor receptor 2 (HER2, p185), has improved outcomes for patients with HER2-positive gastric cancer (GC), but some relevant issues remain to be investigated and will emerge with new anti-GC drugs. Gastrin is a major gastrointestinal hormone proven to have an inhibitory effect on GC in vitro and in vivo.
  
  
  OBJECTIVE
  To explore the sympathetic role of trastuzumab and gastrin on inhibition of GC.
  
  
  METHODS
  The HER2-positive and HER2-negative GC cell lines were treated with trastuzumab, gastrin, or their combination in vitro and in xenograft model. The synergistical role of trastuzumab and gastrin and related mechanisms were investigated.
  
  
  RESULTS
  We found the synergistic inhibitory effects of trastuzumab and gastrin on HER2-negative GC cells through the gastrin/cholecystokinin B receptor (CCKBR) pathway. Trastuzumab upregulated CCKBR protein levels but could not initiate its signal transduction, whereas gastrin increased the levels and activation of CCKBR. Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR. Moreover, their combined treatment synergistically arrested GC cells at G0/G1 phase, down-regulated levels of GC-related proteins, including anion exchanger 1 (AE1), cyclin D1, β-catenin, and cytoplasmic p16, and promoted nuclear translocation of p16. In addition, combination treatment upregulated AE2 levels, which are reduced in GC tissues. The in vivo synergistic anti-GC effect of combined treatment was confirmed in xenograft experiments.
  
  
  CONCLUSIONS
  Trastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.
authors.affiliation: Department of Oncology, Affiliated Hospital of Yanbian University, Yanbian, China.|Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China.
authors.forename: Shao-Bo
authors.initials: SB
authors.lastname: Li
authors.affiliation: Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China.
authors.forename: Xing-Chun
authors.initials: XC
authors.lastname: Peng
authors.affiliation: Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China. Jun.Wu@shsmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Pathology Center, Shanghai First People's Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Number 280, South Chong-Qing Road, Shanghai, 200025, China. guohuifu@shsmu.edu.cn.
authors.forename: Guo-Hui
authors.initials: GH
authors.lastname: Fu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005755:Gastrins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Gastric cancer (GC); Gastrin; Gastrin/cholecystokinin B receptor (CCKBR); HER2; Trastuzumab