STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice
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
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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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 5

STAT3-dependent gastric tumorigenesis is independent of hematopoietic system–mediated antitumor immunity.

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STAT3-dependent gastric tumorigenesis is independent of hematopoietic sy...
(A) Immunohistochemical analysis of pY-STAT3 in 12-week-old mice shows staining toward the base of the glandular gastric epithelium in wild-type and unaffected regions in gp130Y757F/Y757F mice (arrowheads), with extensive epithelial staining throughout the tumors (white arrow, middle panel) and of submucosal inflammatory cell infiltrates (black arrow, right panel). Scale bars: 100 μm. (B) The total wet weight of excised polyps from individual adult gp130Y757F/Y757F mice was determined following a 28-day treatment period with PBS vehicle or STAT3-ASO at the indicated concentration. Two months prior to ASO treatment, 6- to 8-week-old mice with established gastric tumors had been reconstituted with either autologous (F/FF/F) or heterologous gp130+/+ bone marrow (F/F+/+). Reconstituted mice were approximately 18–20 weeks old when sacrificed, and 12- to 14-week-old gp130Y757F/Y757F mice were included to control for potential radiation-mediated alterations to gastric polyp weights. Data are expressed as mean ± SD. n = 8 (naive mice), n = 5 (reconstituted mice). *P < 0.05 versus PBS-treated gp130Y757F/Y757F mice belonging to the corresponding group. ND, not determined.