title: Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression.
abstract: Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression.
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.forename: Louise
authors.initials: L
authors.lastname: O'Connor
authors.forename: Yok Teng
authors.initials: YT
authors.lastname: Chionh
authors.forename: Jan
authors.initials: J
authors.lastname: Däbritz
authors.forename: Michelle
authors.initials: M
authors.lastname: Scurr
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Rollo
authors.forename: Garrett Z
authors.initials: GZ
authors.lastname: Ng
authors.forename: Shelley
authors.initials: S
authors.lastname: Jacobs
authors.forename: Angelique
authors.initials: A
authors.lastname: Catubig
authors.forename: Bayzar
authors.initials: B
authors.lastname: Kurklu
authors.forename: Stephen
authors.initials: S
authors.lastname: Mercer
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
authors.forename: David E
authors.initials: DE
authors.lastname: Ong
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Sutton
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C503073:GKN2 protein, human; C513969:Gkn2 protein, mouse; D009363:Neoplasm Proteins