Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression.
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.
Jackson
C B
CB
Gastrointestinal Cancer Lab, Department of Medicine, The University of Melbourne at Western Hospital, Footscray, 3011, Melbourne, Australia.
Judd
L M
LM
Menheniott
T R
TR
Kronborg
I
I
Dow
C
C
Yeomans
N D
ND
Boussioutas
A
A
Robb
L
L
Giraud
A S
AS
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001706:Biopsy; D049109:Cell Proliferation; D018450:Disease Progression; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D005756:Gastritis / Q000378:metabolism / Q000382:microbiology; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D054328:Proton Pump Inhibitors; D011706:Pyloric Antrum / Q000382:microbiology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D017370:Interleukin-11; D015850:Interleukin-6; D016209:Interleukin-8; D009363:Neoplasm Proteins; D054328:Proton Pump Inhibitors; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C080866:cagA protein, Helicobacter pylori; D048052:Mitogen-Activated Protein Kinase 3