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

Ernst, Matthias, Najdovska, Meri, Grail, Dianne, Lundgren-May, Therese, Buchert, Michael, Tye, Hazel, Matthews, Vance B., Armes, Jane, Bhathal, Prithi S., Hughes, Norman R., Marcusson, Eric G., Karras, James G., Na, Songqing, Sedgwick, Jonathon D., Hertzog, Paul J. and Jenkins, Brendan J. (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. Journal of Clinical Investigation, 118 5: 1727-1738. doi:10.1172/JCI34944

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Author Ernst, Matthias
Najdovska, Meri
Grail, Dianne
Lundgren-May, Therese
Buchert, Michael
Tye, Hazel
Matthews, Vance B.
Armes, Jane
Bhathal, Prithi S.
Hughes, Norman R.
Marcusson, Eric G.
Karras, James G.
Na, Songqing
Sedgwick, Jonathon D.
Hertzog, Paul J.
Jenkins, Brendan J.
Title STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
Publication date 2008-05-01
Year available 2008
Sub-type Article (original research)
DOI 10.1172/JCI34944
Open Access Status DOI
Volume 118
Issue 5
Start page 1727
End page 1738
Total pages 12
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Language eng
Subject 2700 Medicine
Formatted 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.
Keyword Medicine, Research & Experimental
Research & Experimental Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
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