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

• Published in: The Journal of pathology 2011-10, Vol.225 (2), p.255-264
• Main Authors: Kennedy, Catherine L, Najdovska, Meri, Jones, Gareth W, McLeod, Louise, Hughes, Norman R, Allison, Cody, Huey Ooi, Chia, Tan, Patrick, Ferrero, Richard L, Jones, Simon A, Dev, Anouk, Sievert, William, Bhathal, Prithi S, Jenkins, Brendan J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Differentiation - immunology; Cell Separation; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - metabolism; Flow Cytometry; gastric cancer; gastritis; Gastritis - immunology; Gastritis - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Knock-In Techniques; gp130; Humans; IL-17A; IL-6; Immunohistochemistry; Interleukin-17 - biosynthesis; Interleukin-6 - immunology; Interleukin-6 - metabolism; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Reverse Transcriptase Polymerase Chain Reaction; STAT3; STAT3 Transcription Factor - metabolism; Stomach Neoplasms - immunology; Stomach Neoplasms - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Th17 Cells - cytology; Th17 Cells - immunology; Th17 Cells - metabolism; Tumors
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2933

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 (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 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.# Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.