The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17.

Journal Article (Journal Article)

Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130(F/F) mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorγt, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130(F/F) mice were reduced to wild-type levels in gp130(F/F) :Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F) :IL-6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F) :IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.

Full Text

Duke Authors

Cited Authors

  • Kennedy, CL; Najdovska, M; Jones, GW; McLeod, L; Hughes, NR; Allison, C; Ooi, CH; Tan, P; Ferrero, RL; Jones, SA; Dev, A; Sievert, W; Bhathal, PS; Jenkins, BJ

Published Date

  • October 2011

Published In

Volume / Issue

  • 225 / 2

Start / End Page

  • 255 - 264

PubMed ID

  • 21710691

Electronic International Standard Serial Number (EISSN)

  • 1096-9896

Digital Object Identifier (DOI)

  • 10.1002/path.2933

Language

  • eng

Conference Location

  • England