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STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice
Matthias Ernst, … , Paul J. Hertzog, Brendan J. Jenkins
Matthias Ernst, … , Paul J. Hertzog, Brendan J. Jenkins
Published April 22, 2008
Citation Information: J Clin Invest. 2008;118(5):1727-1738. https://doi.org/10.1172/JCI34944.
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Research Article

STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice

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Abstract

Deregulated activation of STAT3 is frequently associated with many human hematological and epithelial malignancies, including gastric cancer. While exaggerated STAT3 signaling facilitates an antiapoptotic, proangiogenic, and proproliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 hyperactivation remain poorly understood. Using the gp130Y757F/Y757F mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130Y757F/Y757F mice, when compared with unaffected gastric tissue in wild-type mice, while gp130Y757F/Y757F mice lacking the IL-11 ligand–binding receptor subunit (IL-11Rα) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130Y757F/Y757F mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130Y757F/Y757F mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1.

Authors

Matthias Ernst, Meri Najdovska, Dianne Grail, Therese Lundgren-May, Michael Buchert, Hazel Tye, Vance B. Matthews, Jane Armes, Prithi S. Bhathal, Norman R. Hughes, Eric G. Marcusson, James G. Karras, Songqing Na, Jonathon D. Sedgwick, Paul J. Hertzog, Brendan J. Jenkins

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Figure 4

Reduced STAT3 activation and gastric tumor burden in STAT3-ASO–treated gp130Y757F/Y757F mice.

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Reduced STAT3 activation and gastric tumor burden in STAT3-ASO–treated g...
(A) Blood platelet counts of naive adult gp130Y757F/Y757F mice treated with either vehicle (PBS) or STAT3-ASO at the indicated concentrations every second day over 28 days. Data are expressed as mean ± SD. n = 8 for each treatment group. *P < 0.05 versus vehicle-treated mice. (B) Representative whole-mount appearance of stomachs from mice shown in A. Mice were treated either with vehicle or 50 mg/kg STAT3-ASO. Data points represent the combined wet weight of all excised polyps from individual mice, and the horizontal lines indicate the means. (C and D) Tissue cross-sections of gastric polyps from mice shown in B and stained with either H&E (C) or an antibody against BrdU (D). Scale bars: 100 μm. (E) Immunoblot analyses of antral gastric tissue lysates from individual naive gp130Y757F/Y757F mice using the indicated antibodies. Mice were treated with PBS, control-ASO, or STAT3-ASO at a final concentration of 50 mg/kg, and each lane represents an individual mouse. (F) Q-PCR analyses of Socs3 and Il11 gene expression in gastric tumors from mice shown in E and treated with either control ASO or STAT3-ASO at 50 mg/kg. Data are expressed as mean ± SD. n = 5 for each treatment group. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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