Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression
Author(s)
Menheniott, Trevelyan R.; O’Connor, Louise; Chionh, Yok Teng; Däbritz, Jan; Scurr, Michelle; Rollo, Benjamin N.; Ng, Garrett Z.; Jacobs, Shelley; Catubig, Angelique; Kurklu, Bayzar; Mercer, Stephen; Minamoto, Toshinari; Ong, David E.; Ferrero, Richard L.; Wang, Timothy C.; Sutton, Philip; Judd, Louise M.; Giraud, Andrew S.; Fox, James G; ... Show more Show less
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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 gp130[superscript F/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 gp130[superscript F/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.
Date issued
2016-03Department
Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Division of Comparative MedicineJournal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Citation
Menheniott, Trevelyan R., Louise O’Connor, Yok Teng Chionh, Jan Däbritz, Michelle Scurr, Benjamin N. Rollo, Garrett Z. Ng, et al. “Loss of Gastrokine-2 Drives Premalignant Gastric Inflammation and Tumor Progression.” Journal of Clinical Investigation 126, no. 4 (March 14, 2016). © 2016 American Society for Clinical Investigation
Version: Final published version
ISSN
0021-9738
1558-8238