Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression

Jackson, CB; Judd, LM; Menheniott, TR; Kronborg, I; Dow, C; Yeomans, ND; Boussioutas, A; Robb, L; Giraud, AS

Author(s): Jackson, CB; Judd, LM; Menheniott, TR; Kronborg, I; Dow, C; Yeomans, ND; Boussioutas, A; Robb, L; Giraud, AS;
Details: Publication Year 2007-10,Volume 213,Issue #2,Page 140-151
Journal Title: JOURNAL OF PATHOLOGY
Publication Type: Journal Article
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; (iii) 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. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: JOHN WILEY & SONS LTD
Keywords: HELICOBACTER-PYLORI INFECTION; GP130 MUTANT MICE; NF-KAPPA-B; EPITHELIAL-CELLS; CAGA PROTEIN; STAT3 ACTIVATION; CONSTITUTIVE ACTIVATION; TYROSINE-PHOSPHATASE; IN-VIVO; EXPRESSION
Publisher's Version: https://doi.org/10.1002/path.2218
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Creation Date: 2007-10-01 12:00:00