Augmented gp130‐mediated cytokine signalling accompanies human gastric cancer progression

Journal of Pathology - Tập 213 Số 2 - Trang 140-151 - 2007
CB Jackson1, Louise M. Judd1, Trevelyan R. Menheniott1, Ian Kronborg2, Chris Dow3, Neville D. Yeomans4, Alex Boussioutas2,1, Lorraine Robb5, AS Giraud1
1Gastrointestinal Cancer Lab, Department of Medicine, The University of Melbourne at Western Hospital, Footscray, 3011, Melbourne, Australia
2Gastroenterology Unit, Western Hospital, Footscray, Melbourne, 3011, Australia
3Pathology Department, Western Hospital, Footscray, Melbourne, 3011, Australia
4Faculty of Medicine, University of Western Sydney, Sydney, 1797, Australia
5Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050, Australia

Tóm tắt

AbstractH. 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 gp130757FF 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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Journal of Pathology

Tập 213 Số 2

140-151

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