A4gnt-Deficient Mice Show Enhanced IL-11 Receptor α-Glycoprotein 130-Janus Kinase 2-STAT3 Signaling in Early Stages of Gastric Tumorigenesis: Comparative Analysis with A4gnt and Il11 Doubly Deficient Mice.

Gastric mucins contain O-glycans carrying terminal α1,4-linked N-acetylglucosamine (αGlcNAc). A previous study demonstrated that A4gnt-deficient mice lack αGlcNAc, spontaneously develop differentiated-type gastric adenocarcinoma, and exhibit significant up-regulation of Il11 transcripts in gastric mucosa. This study assessed mechanisms by which αGlcNAc deficiency induces tumorigenesis, focusing on the IL-11 receptor α (IL-11Rα)-glycoprotein 130 (gp130)-Janus kinase 2 (JAK2)-STAT3 axis. A4gnt-deficient mice exhibited enhanced phosphorylation of JAK2 and STAT3 in pyloric mucosa compared with wild-type mice, with significant increases in JAK2 phosphorylation at 5 weeks and in STAT3 phosphorylation at 5 and 10 weeks. IL-11Rα and gp130 proteins significantly increased during this period. The thickness of the pyloric gland cell layer was significantly decreased in A4gnt and Il11 doubly deficient (A4gnt-/-;Il11-/-) mice at 10 but not 30 weeks compared with A4gnt-deficient mice, suggesting an IL-11 requirement in the early stage of tumorigenesis. Significant reduction of the proportion of phosphorylated STAT3-positive nuclei in pyloric mucosa of A4gnt-/-;Il11-/- mice at 10 weeks supports the IL-11-mediated phosphorylated STAT3 involvement in this stage. Analysis of gastric cancer AGS-A cells overexpressing αGlcNAc using a Tet-On system revealed significant reduction of IL-11-induced STAT3 phosphorylation compared with αGlcNAc-negative conditions. Moreover, both IL-11Rα and gp130 from wild-type mice and αGlcNAc-expressing AGS-A cells carried αGlcNAc, suggesting that the presence of αGlcNAc on these proteins interferes with receptor-complex formation. These findings indicate αGlcNAc protects gastric mucosa from inflammation-induced tumorigenesis by regulating IL-11Rα-gp130-JAK2-STAT3 signaling.