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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 1

Increased expression of IL-11 and other gp130 family cytokines in gastric tumors of gp130Y757F/Y757F mice.

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Increased expression of IL-11 and other gp130 family cytokines in gastri...
(A) Quantitative RT-PCR (Q-PCR) analyses of Il11, Il6, and Lif gene expression were performed on cDNA derived from total RNA prepared from antral gastric tissue of 14-week-old gp130+/+ wild-type (+/+) and gp130Y757F/Y757F (F/F) mice. Expression data from 3–5 samples per genotype following normalization for 18S expression are shown and are presented from replicate analysis as the mean fold induction ± SD relative to expression observed in gp130+/+ samples. (B) Immunoblot analyses were performed on lysates prepared from antral gastric tissue of gp130+/+ and gp130Y757F/Y757F mice using the indicated antibodies. Each lane represents tissue from an individual mouse. Densitometric quantitation of IL-11 in each of 3 representative samples per genotype was performed and normalized against ERK1/2 protein levels. Data are presented as the mean fold induction ± SD relative to expression in gp130+/+ samples. (C) Q-PCR gene expression analyses of Il6ra, Il11ra1, and gp130 as in A. *P < 0.05 versus expression in gp130+/+ samples.

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

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