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Gilead Sciences.

and PV Desmond have no conflicts of interest to declare. P De Cruz has received travel grant support from Abbott and Schering-Plough. MA Kamm has acted as an advisor to Abbott and Janssen, has received research support from Abbott, and has acted as a speaker at symposiums sponsored by Abbott and Janssen. A Hamilton has received an educational grant from Abbott. D Liew has served on advisory boards and received research grants from Abbott. IC Lawrance has been on an advisory board for Abbott and Janssen, a speaker for Abbott and Janssen, and has held research and travel grants from Abbott and Janssen. JM Andrews has been an advisory board member for both Janssen and Abbott, spoken for both Abbott and Janssen, received research funds from both Abbott and Janssen, and received travel grants from both Abbott and Janssen. PA Bampton has been on advisory boards for Janssen and Abbott, has received research funding from Abbott, and travel sponsorship from both Abbott and Janssen. PR Gibson has received consulting fees from Abbott, Janssen, and Schering-Plough; research support from Abbott; and payments for lectures from Abbott and Janssen. FA Macrae has been on an advisory board to Janssen, has received travel grants from Abbott, and has received clinical research support from Janssen, Abbott and MSD. W Selby has been on an advisory board for Abbott. SJ Bell has received travel assistance from Abbott. SJ Brown has received travel support and speaker fees from both Abbott and Janssen. WR Connell has been on advisory board for Janssen and a speaker for Abbott and Janssen. AS Day has been an M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT advisor to Janssen. RB Gearry has been on an advisory board for Abbott and Janssen, a speaker for Abbott and Janssen, and held research, educational and travel grants from Abbott and Janssen.

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.