Galectin-3 is Necessary for Selective Cathartocytosis, which Expedites the Development of Proliferative Gastric SPEM

Abstract

The expression and secretion of sulfated colonic-type mucins is a feature of high-risk metaplasias of the gastrointestinal foregut (Barretts esophagus, type III intestinal metaplasia of the stomach, and pancreatic intraepithelial neoplasia). Galectin-3 is a lectin that preferentially associates with galactose modified by a 3-O-sulfate relative to its unmodified counterparts and is upregulated as the tissue transitions to high-risk metaplasia, dysplasia, and cancer. Since both galectin-3 and sulfated glycotopes are aberrantly and concurrently overexpressed in high-risk premalignant and malignant tissue transformations, we sought to investigate the role of galectin-3 in the metaplastic reaction. We found that injury induces the expression of Lgals3 at the RNA and protein levels. Unlike cancer cell lines, we show that in vivo galectin-3 colocalized with sulfomucins in zymogenic granules of the gastric chief cell. Utilizing a synchronous, chemically-induced murine model that produces spasmolytic polypeptide expressing metaplasia, we found that galectin-3 facilitates cathartocytosis of the vesicles it resides in, but not organelles lacking LGALS3. Inhibition of cellular downscaling resulted in delayed expression of the metaplastic transcription factor Sox9 as well as proliferation. Here, we present a new role for galectin-3 in promoting the transition from normal, homeostatic tissue to metaplasia and our data suggest that cathartocytosis represents an unconventional secretory pathway for galectin-3, which has been a matter of controversy as galectins are not secreted via canonical pathways.