Signaling mediated by the NF-κB sub-units NF-κB1, NF-κB2 and c-Rel differentially regulate Helicobacter felis-induced gastric carcinogenesis in C57BL/6 mice

Research output: Contribution to journalArticlepeer-review

Authors

  • M D Burkitt
  • J M Williams
  • C A Duckworth
  • A O'Hara
  • A Hanedi
  • A Varro
  • D M Pritchard

Colleges, School and Institutes

External organisations

  • Department of Gastroenterology, The Henry Wellcome Laboratories, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
  • University of Liverpool
  • School of Immunity and Infection, IBR-MRC Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham.

Abstract

The classical nuclear factor-kappaB (NF-κB) signaling pathway has been shown to be important in a number of models of inflammation-associated cancer. In a mouse model of Helicobacter-induced gastric cancer, impairment of classical NF-κB signaling in the gastric epithelium led to the development of increased preneoplastic pathology, however the role of specific NF-κB proteins in Helicobacter-associated gastric cancer development remains poorly understood. To investigate this C57BL/6, Nfkb1(-/-), Nfkb2(-/-) and c-Rel(-/-) mice were infected with Helicobacter felis for 6 weeks or 12 months. Bacterial colonization, gastric atrophy and preneoplastic changes were assessed histologically and cytokine expression was assessed by qPCR. Nfkb1(-/-) mice developed spontaneous gastric atrophy when maintained for 12 months in conventional animal house conditions. They also developed more pronounced gastric atrophy after short-term H. felis colonization with a similar extent of preneoplasia to wild-type (WT) mice after 12 months. c-Rel(-/-) mice developed a similar degree of gastric atrophy to WT mice; 3 of 6 of these animals also developed lymphoproliferative lesions after 12 months of infection. Nfkb2(-/-) mice developed minimal gastric epithelial pathology even 12 months after H. felis infection. These findings demonstrate that NF-κB1- and NF-κB2-mediated signaling pathways differentially regulate the epithelial consequences of H. felis infection in the stomach, while c-Rel-mediated signaling also appears to modulate the risk of lymphomagenesis in gastric mucosa-associated lymphoid tissue.

Details

Original languageEnglish
Pages (from-to)5563-73
Number of pages11
JournalOncogene
Volume32
Issue number50
Publication statusPublished - 12 Dec 2013

Keywords

  • Animals, Cell Transformation, Neoplastic/metabolism, Disease Models, Animal, Female, Gastric Mucosa/metabolism, Gene Deletion, Helicobacter Infections/complications, Helicobacter felis, Inflammation/genetics, Mice, Mice, Knockout, NF-kappa B/chemistry, NF-kappa B p50 Subunit/genetics, NF-kappa B p52 Subunit/genetics, Proto-Oncogene Proteins c-rel/metabolism, Signal Transduction, Stomach Neoplasms/etiology