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

Kennedy, Catherine L., Najdovska, Meri, Jones, Gareth Wyn, McLeod, Louise, Hughes, Norman R., Allison, Cody, Huey Ooi, Chia, Tan, Patrick, Ferrero, Richard L., Jones, Simon Arnett, Dev, Anouk, Sievert, William, Bhathal, Prithi S. and Jenkins, Brendan J. 2011. The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17. The Journal of Pathology 225 (2) , pp. 255-264. 10.1002/path.2933

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Abstract

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 gp130F/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 gp130F/F mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rort, 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 gp130F/F mice were reduced to wild-type levels in gp130F/F:Stat3−/+ mice displaying normalized STAT3 activity, and also in gp130F/F:IL-6−/− mice. Importantly, genetic ablation of IL-17A in gp130F/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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	gastritis, gastric cancer, gp130, IL-6, IL-17A, STAT3
Publisher:	Wiley
ISSN:	0022-3417
Last Modified:	06 Aug 2019 22:10
URI:	http://orca-mwe.cf.ac.uk/id/eprint/22929

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