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.

Heterodimeric interaction between GKN2 and TFF1 entails synergistic antiproliferative and pro-apoptotic effects on gastric cancer cells

“…1b, c, Supplementary Figure S1 in the ESM). These results are consistent with those of previous studies reporting that GKN2 alone does not affect cell growth [15] and that GKN2 −/− mice show no evidence of significant epithelial hyperplasia or spontaneous gastric tumors [20]. Thus, GKN2 may be able to acquire growth-inhibiting properties by interacting with TFF1, thereby facilitating the antiproliferative impact of the latter.…”

“…It seems that GKN2, when acting as a protein partner to TFF1, may be involved in the regulation of important anticarcinogenic effects of TFF1. Although GKN2 has been identified as a gastric tumor suppressor [19, 20], the precise roles of GKN2 alone and when interacting with TFF1 are poorly understood.…”

GKN2 promotes oxidative stress-induced gastric cancer cell apoptosis via the Hsc70 pathway

“…The heterodimeric interaction between GKN2 and TFF1 played an important in inhibition of GC [29]; thereafter, its anti-proliferative and pro-apoptotic effects on GC cells were further substantiated and other mechanisms of GKN2 action emerged [30], including the recent indication that GKN2 functions as a GKN1 inhibitor, contributing to the homeostasis of gastric mucosa. GKN2 also play a significant role in regulation of gastric inflammation [31].…”

Helicobacter: Inflammation, immunology and vaccines

“…Gastrokine-2 (GKN2) was shown to have an anti-inflammatory function and involvement in the regulation of mucosal Th1 responses. 16 Th1 cells and gastric pathology were increased in H. pylori-infected Gkn2 −/− mice, while innate immunity was dysregulated and myeloid suppressor cell responses reduced. In contrast, Yao et al 17 reported that H. pylori-upregulated expression of serum and glucocorticoidinducible kinase 1, induces Th17 and Th2 differentiation and reduces Th1 responses.…”

“…H. pylori persists by manipulating this response; however, the underlying mechanisms are not fully understood. Gastrokine‐2 (GKN2) was shown to have an anti‐inflammatory function and involvement in the regulation of mucosal Th1 responses . Th1 cells and gastric pathology were increased in H. pylori ‐infected Gkn2 −/− mice, while innate immunity was dysregulated and myeloid suppressor cell responses reduced.…”