title: The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17.
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 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.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Kennedy
authors.forename: Meri
authors.initials: M
authors.lastname: Najdovska
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.forename: Norman R
authors.initials: NR
authors.lastname: Hughes
authors.forename: Cody
authors.initials: C
authors.lastname: Allison
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Anouk
authors.initials: A
authors.lastname: Dev
authors.forename: William
authors.initials: W
authors.lastname: Sievert
authors.forename: Prithi S
authors.initials: PS
authors.lastname: Bhathal
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005756:Gastritis / Q000276:immunology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor