Details

Autor(en) / Beteiligte

• Howlett, Meegan
• Giraud, Andrew S
• Lescesen, Helen
• Jackson, Cameron B
• Kalantzis, Anastasia
• Van Driel, Ian R
• Robb, Lorraine
• Van der Hoek, Mark
• Ernst, Matthias
• Minamoto, Toshinari
• Boussioutas, Alex
• Oshima, Hiroko
• Oshima, Masanobu
• Judd, Louise M

Titel

The Interleukin-6 Family Cytokine Interleukin-11 Regulates Homeostatic Epithelial Cell Turnover and Promotes Gastric Tumor Development

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2009-03, Vol.136 (3), p.967-977.e3

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2009

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Background & Aims Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer. Methods We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis. Results IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor α significantly reduced HKβ-/- mouse fundic hyperplasia and ablated gp130757F/F mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-β, RegIII-γ, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130757F/F and HKβ-/- tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus. Conclusions Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.