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

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 8

STAT3 and STAT1 induce gastric IL-11 gene expression.

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STAT3 and STAT1 induce gastric IL-11 gene expression. (A) Q-PCR on antra...
(A) Q-PCR on antral gastric cDNA prepared from untreated gp130Y757F/Y757F mice, as well as gp130+/+ mice either untreated or injected with a single dose of recombinant IL-11 or IFN-α. Expression data following normalization for 18S expression are shown and are presented from replicate analysis as the mean fold induction ± SD relative to expression in gp130+/+ samples. n = 3 mice per genotype and treatment. *P < 0.05 versus expression in untreated gp130+/+ samples. (B) Immunoblot analysis of total STAT3 and tyrosine-phosphorylated STAT3 in antral gastric tissue lysates from mice shown in A. (C) Transcriptional activation of the mouse Il11 gene in wild-type MEFs following transient transfection of the pIL11-luc firefly luciferase reporter construct. Triplicate cultures of cells, cotransfected with pTK-RL, were stimulated with the indicated amount of recombinant IFN-α, IFN-γ, or HYPERIL-6. Luciferase activity was determined 48 hours later and normalized against activity of the Renilla luciferase reporter and expressed relative to unstimulated control cultures. pAPRE-luc and pISRE-luc transfectants were used to assess for specific STAT3- and STAT1-mediated reporter activation. Data are representative of replicate analyses and are expressed as means of fold changes relative to unstimulated controls ± SD. *P < 0.05 versus expression in unstimulated cultures. (D) Schematic representation of pIL11-luc reporter plasmid depicting positions of potential STAT3 (top) and STAT1 (bottom) binding sites relative to the 5′ end of exon 1 of the mouse Il11 gene. The palindromic core motifs of the STAT binding sites are indicated in upper-case letters, and spacer sequences are indicated in lower-case letters.