Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression
Trevelyan R. Menheniott, … , Louise M. Judd, Andrew S. Giraud
Trevelyan R. Menheniott, … , Louise M. Judd, Andrew S. Giraud
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1383-1400. https://doi.org/10.1172/JCI82655.
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Research Article Oncology

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

Trevelyan R. Menheniott, Louise O’Connor, Yok Teng Chionh, Jan Däbritz, Michelle Scurr, Benjamin N. Rollo, Garrett Z. Ng, Shelley Jacobs, Angelique Catubig, Bayzar Kurklu, Stephen Mercer, Toshinari Minamoto, David E. Ong, Richard L. Ferrero, James G. Fox, Timothy C. Wang, Philip Sutton, Louise M. Judd, Andrew S. Giraud

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Figure 3

Gkn2–/– mice display impaired basal gastric epithelial differentiation.

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Gkn2–/– mice display impaired basal gastric epithelial differentiation....
(A) Representative images of the gastric mucosa of 6-, 12-, and 30-week-old Gkn2–/– and WT littermate control mice. Boundaries between corpus and antral mucosae are delineated with white dashed lines; hypertrophic mucosal lesions are shown by black dashed lines. Scale bar: 5 mm. (B) Low-power images showing AB-PAS–stained Gkn2–/– hypertrophic lesions compared with nonlesion and WT corpus mucosa. Scale bar: 200 μm. High-power images of corpus and antrum mucosa in 12-week-old Gkn2–/– and WT mice. Scale bar: 50 μm. (C) Summary of semiquantitative histopathology scores for corpus inflammation (inflamm), atrophy, MNC hyperplasia (MNC hyp), and SMC metaplasia (SMC met) in 6-, 12-, and 30-week-old WT and Gkn2–/– mice (group sizes as stated in D). (D) Morphometric analysis of corpus and antral mucosal thickness in 6-, 12-, and 30-week-old Gkn2–/– (n = 11, n = 9, n = 7) and WT mice (n = 7, n = 9, n = 8). Histograms show mean mucosal thickness as histological cross-sectional area/mm2 per mm length of muscularis mucosae. (E) Ki-67 labeling of proliferating cells in corpus mucosa of 6-, 12-, and 30-week-old WT and Gkn2–/– mice and antral mucosa of 12-week-old WT and Gkn2–/– mice (n = 6 per group). Representative images of 12-week-old WT and Gkn2–/– corpus and Gkn2–/– lesion mucosa are shown. Scale bar: 100 μm. Error bars represent mean ± SEM. P values were determined using a 2-tailed Student’s t test: *P < 0.05; **P < 0.01; ***P < 0.001.