Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nucle...

Full description

Saved in:
Bibliographic Details
Published in:The American journal of pathology Vol. 190; no. 6; p. 1256
Main Authors: Balic, Jesse J, Saad, Mohamed I, Dawson, Ruby, West, Alice J, McLeod, Louise, West, Alison C, D'Costa, Kimberley, Deswaerte, Virginie, Dev, Anouk, Sievert, William, Gough, Daniel J, Bhathal, Prithi S, Ferrero, Richard L, Jenkins, Brendan J
Format: Journal Article
Language:English
Published: United States 01.06.2020
ISSN:1525-2191, 1525-2191
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3 mice with chronic H. felis infection, which mimics human H. pylori infection in mice, 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 gastritis was markedly suppressed in infected Stat3 mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3 mice, which was associated with reduced proliferative potential of infected Stat3 gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3 mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1525-2191
1525-2191
DOI:10.1016/j.ajpath.2020.01.021