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Am J Pathol. 2020 Mar 19. pii: S0002-9440(20)30134-6. doi: 10.1016/j.ajpath.2020.01.021. [Epub ahead of print]

Constitutive STAT3 serine phosphorylation promotes Helicobacter-mediated gastric disease.

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria, 3168, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia.
2
Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia.
3
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
4
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia.
5
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria, 3168, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
6
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria, 3168, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia. Electronic address: Brendan.Jenkins@hudson.org.au.

Abstract

Gastric cancer is associated with chronic inflammation (gastritis) triggered by infection with the Helicobacter pylori (H. pylori) bacterium. Elevated tyrosine phosphorylation (pY) of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and is aligned to nuclear transcriptional activity. By contrast, the transcriptional role of STAT3 serine phosphorylation (pS), which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling pS-STAT3-deficient Stat3SA/SA mice with chronic H. felis infection, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells, and expression analyses of inflammatory genes, revealed that chronic gastritis was markedly suppressed in infected Stat3SA/SA mice compared to wild-type (WT) mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3SA/SA (compared to WT) mice, which was associated with reduced proliferative potential of infected Stat3SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumourigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic gene networks. In gastric mucosa of mice and gastritis patients, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.

KEYWORDS:

Helicobacter pylori; STAT3; gastritis; hyperplasia; intestinal metaplasia; serine phosphorylation; transcriptional regulation

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