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 ORCID: https://orcid.org/0000-0001-7297-9711, 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:	05 Nov 2022 15:20
URI:	https://orca.cardiff.ac.uk/id/eprint/22929

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