Galectin-8 Modulates Membrane CD44v Localization and Tempers STAT3 Signaling in Gastric Metaplasia

ABSTACTGalectin-8 is a lectin that binds N-acetyllactosamine moieties with preference towards those with acidic, terminal modifications (-O-sialyated, 3-O-sulfated). As CD44-variants (CD44v) are biomarkers of metaplasia and cancer, a hyaluronic acid receptor that modulates STAT3 signaling, and specifically expresses 3-Sialyl-LeA/X glycotopes, we asked whether galectin-8 might play a role in gastric metaplasia. Using a synchronous, chemically induced murine model that produces gastric spasmolytic polypeptide expressing metaplasia (SPEM), we compared Lgals8-/- mice to congenic wild-type C57BL/6J mice. We found that galectin-8 was necessary for membrane localization of CD44v on SPEM cells at the base of the glands, suggesting a physical interaction between galectin-8 and CD44v. Metaplastic glands from Lgals8-/- mice had an increase in nuclear pSTAT3 compared to C57BL/6J mice, suggesting that galectin-8 restrains CD44 -> STAT3 signaling. This effect was more prominent in the neck compared to the base, which has greater abundance of CD44v after injury in Lgals8-/- mice. Derepression of STAT3 signaling may explain why low galectin-8 levels is associated with a worse prognosis in gastric cancer.