Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression

J Pathol. 2007 Oct;213(2):140-51. doi: 10.1002/path.2218.

Abstract

H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130(757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / microbiology
  • Adenocarcinoma / pathology
  • Antigens, Bacterial / metabolism
  • Bacterial Proteins / metabolism
  • Biopsy
  • Cell Proliferation
  • Disease Progression
  • Enzyme Activation
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / microbiology
  • Gastritis / metabolism
  • Gastritis / microbiology
  • Gene Expression Regulation, Neoplastic
  • Helicobacter Infections / complications
  • Helicobacter pylori
  • Humans
  • Interleukin-11 / metabolism
  • Interleukin-6 / metabolism*
  • Interleukin-8 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neoplasm Proteins / metabolism
  • Proton Pump Inhibitors
  • Pyloric Antrum / microbiology
  • Pyloric Antrum / pathology
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / immunology*
  • Stomach Neoplasms / microbiology
  • Stomach Neoplasms / pathology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Interleukin-11
  • Interleukin-6
  • Interleukin-8
  • Neoplasm Proteins
  • Proton Pump Inhibitors
  • SOCS3 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • cagA protein, Helicobacter pylori
  • Mitogen-Activated Protein Kinase 3