Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease

被引：19

作者：

Balic, Jesse J. ^{[1
,3
]}

Saad, Mohamed, I ^{[1
,3
]}

Dawson, Ruby ^{[1
,3
]}

West, Alice J. ^{[1
,3
]}

McLeod, Louise ^{[1
,3
]}

West, Alison C. ^{[1
,3
]}

D'Costa, Kimberley ^{[1
,3
]}

Deswaerte, Virginie ^{[1
,3
]}

Dev, Anouk ^{[5
]}

Sievert, William ^{[5
]}

Gough, Daniel J. ^{[2
,3
]}

Bhathal, Prithi S. ^{[3
]}

Ferrero, Richard L. ^{[1
,3
,4
]}

Jenkins, Brendan J. ^{[1
,3
]}

机构：

[1] Hudson Inst Med Res, Ctr Innate Immun & Infect Dis, 27-31 Wright St, Clayton, Vic 3168, Australia

[2] Hudson Inst Med Res, Ctr Canc Res, Clayton, Vic, Australia

[3] Monash Univ, Fac Med Nursing & Hlth Sci, Dept Mol Translat Sci, Biomed Discovery Inst, Clayton, Vic, Australia

[4] Monash Univ, Biomed Discovery Inst, Dept Microbiol, Clayton, Vic, Australia

[5] Monash Hlth, Dept Gastroenterol & Hepatol, Melbourne, Vic, Australia

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2020年 / 190卷 / 06期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

MITOCHONDRIAL STAT3; CANCER PROGRESSION; PROTEIN-KINASE; PYLORI; FELIS; MICE; TUMORIGENESIS; INFECTION; IDENTIFICATION; TRANSCRIPTION;

D O I：

10.1016/j.ajpath.2020.01.021

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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(SA/SA) 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(SA/SA) mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3(SA/SA) mice, which was associated with reduced proliferative potential of infected Stat3(SA/SA) gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3(SA/SA) 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.

引用

页码：1256 / 1270

页数：15

共 49 条

[1]

[Anonymous], GASTROENTEROL RES PR

[2] CD44 Plays a Functional Role in Helicobacter pylori-induced Epithelial Cell Proliferation [J].