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

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 in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor alpha significantly reduced HKbeta-/- 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 HKbeta-/- 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.

authors

  • 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

publication date

  • March 2009

has subject area