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 7

Accelerated progression to atrophic gastritis and mucus metaplasia in Gkn2–/– mice after 2-month H. pylori infection.

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Accelerated progression to atrophic gastritis and mucus metaplasia in Gk...
(A) Strategy used for 2-month H. pylori SS1 infections. (B) Macroscopic and histological images of Gkn2–/– and WT littermate stomachs infected for 2 months and uninfected control stomachs. White dashed lines delineate corpus/antrum boundaries. Arrows show the region of corpus hypertrophy in the infected Gkn2–/– stomach macroscopic photo. Scale bar: 5 mm (macroscopic images); 50 μm (histological images). (C) Semiquantitative histological assessment of gastric histopathology: inflammatory infiltrate (polymorphonuclear cells [PMN]; mononuclear cells [MN]), atrophy (degree of parietal/zymogenic cell loss), and mucus metaplasia (Met). Histograms show mean pathology scores for each parameter (range 0–4). (D) QRT-PCR analysis of metaplasia (Muc6) and glandular atrophy–related (Mist1 and HKβ) genes in Gkn2–/– mice after 2 months of H. pylori infection. Histograms show mean mRNA fold change relative to WT uninfected mice. (E) H. pylori SS1 colonization levels in stomachs after 2 months of infection, as assessed by Q-PCR (Supplemental Methods). Histograms show mean colonization level (104 H. pylori genomes per 105 Gapdh copies). (F) Linear regression analysis of corpus inflammation score and colonization level. The correlation coefficient (r2) value is shown. Error bars represent mean ± SEM. P values were determined using a 2-tailed Student’s t test (C) or 2-tailed Mann Whitney U test (D and E). Statistical significance compared with WT uninfected control mice: #P < 0.05. Statistical significance between treatment groups: *P < 0.05; **P < 0.01; ***P < 0.001.