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PWE-063 Epidermal growth factor receptor inhibitor reduces helicobacter-induced upregulation of gastric activation-induced cytidine deaminase in the murine INS-GAS cancer model
  1. C Duval1,
  2. M D Pritchard2,
  3. A Abu Derman2,
  4. A Varro3,
  5. P A Robinson1,
  6. J E Crabtree1
  1. 1Institute of Molecular Medicine, St James Hospital, Leeds, UK
  2. 2Division of Gastroenterology, University of Liverpool, Liverpool, UK
  3. 3Department of Physiology, University of Liverpool, Liverpool, UK


Introduction Gastric infection with Helicobacter in transgenic hypergastrinaemic INS-GAS mice has been shown to accelerate the development of gastric cancer. Both H pylori and gastrin transactivate the EGF receptor (EGFR) in an autocrine or paracrine manner, respectively. The aims of the study were to examine the effects of treatment with an EGFR inhibitor in H felis infected INS-GAS mice.

Methods Male INS-GAS mice were orally infected with H felis. Six weeks post-infection, infected and uninfected controls were fed either control, or EKB-569 (EGF inhibitor) supplemented food. Mice were sacrificed at 9 months post-infection. At post mortem gastric tissue was taken for pathology, analysis of RNA, proteins and DNA. Mucosal thickness and gastric epithelial cell proliferation (Mib1), apoptosis (active caspase 3), parietal cell density (H+K+ ATPase), B cell density (CD20) and Aicda (activation-induced cytidine deaminase, a DNA editing enzyme) were assessed immunohistologically. Gene expression was determined by quantitative RT-PCR.

Results H felis infection resulted in significant increases in corpus mucosal thickness, Mib1 positive epithelial cells, active caspase 3 positive epithelial cells, and reduced number of parietal cells relative to uninfected controls. EKB-569 had no effect on epithelial proliferation, apoptosis, parietal cell number and mucosal thickness. Infection was associated with increased levels of transcripts for Cox-2, Egfr, Hb-egf, γ-Ifn (1.5–3.5-fold increase, p<0.05), and a marked increase in transcripts of CD20 and Aicda (17 and 18-fold increase, respectively, p<0.001). Transcript levels of Cox-2 and Hb-egf were not altered by EKB-569 treatment and Egfr transcripts were significantly increased (p<0.05). In contrast, EKB-569 induced a marked reduction (p<0.002) in Aicda transcripts, but not in gastric CD20 transcript levels. In EKB-569 treated infected mice there was a strong correlation between Aicda and CD20 mRNA expression (r=0.73), which was absent in untreated infected mice (r=0.02), implying a non-B cell origin of Aicda in untreated mice. Immunohistology confirmed marked upregulation of Aicda in the hyperplastic epithelial cells of the corpus mucosa of infected untreated mice compared to controls.

Conclusion In this study, EKB-569 did not affect gastric pathology, but markedly reduced Helicobacter induced aberrant expression of Aicda, a DNA editing enzyme, shown to induce TP53 mutations in human gastric epithelial cells in vitro.

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