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

Howlett, M; Giraud, AS; Lescesen, H; Jackson, CB; Kalantzis, A; van Driel, IR; Robb, L; Van der Hoek, M; Ernst, M; Minamoto, T; Boussioutas, A; Oshima, H; Oshima, M; Judd, LM

Author(s): Howlett, M; Giraud, AS; Lescesen, H; Jackson, CB; Kalantzis, A; van Driel, IR; Robb, L; Van der Hoek, M; Ernst, M; Minamoto, T; Boussioutas, A; Oshima, H; Oshima, M; Judd, LM;
Details: Publication Year 2009-03,Volume 136,Issue #3,Page 967-977
Journal Title: GASTROENTEROLOGY
Publication Type: Journal Article
Abstract: 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 m human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor a significantly reduced HK beta-/- mouse fundic hyperplasia and ablated gp130(757F/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-beta, RegIII-gamma, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130(757F/F) and HK beta-/- 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.
Publisher: W B SAUNDERS CO-ELSEVIER INC
Keywords: HELICOBACTER-PYLORI; CORECEPTOR GP130; GENE-EXPRESSION; CARCINOMA CELLS; IL-11 RECEPTOR; CANCER CELLS; BETA-SUBUNIT; MUTANT MICE; PROTEIN; GROWTH
Publisher's Version: https://doi.org/10.1053/j.gastro.2008.12.003
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-03-01 12:00:00