Ectopic Expression of Core 3 Synthase in Human Pancreatic Cancer Cells Suppresses Tumor Formation and Metastasis

Core 3 derived glycans, a major type of O-glycans expressed in normal epithelial cells of the gastrointestinal tract, are downregulated during malignancy. To investigate functions of core 3 glycans, we ectopically expressed β3-N-acetylglucosaminyltransferase-6 (core 3 synthase) in human pancreatic cancer cells (Capan-2 and FG). Pancreatic cancer cells expressing core 3 synthase showed reduced in vitro cell proliferation, migration and invasion compared with vector control cells. We also found that core 3 O-glycans altered expression of α2β1 integrin, decreased activation of focal adhesion kinase, and altered lamellipodia formation. Orthotopic injections of FG cells expressing core 3 synthase into pancreases of nude mice produced significantly smaller tumors and decreased metastasis to the surrounding tissues compared to vector control FG cells. Additionally, we observed that the addition of GlcNAc residue by core 3 synthase led to extension of Tn epitope on MUC1 and the down regulation of REG1α. These findings indicate that expression of core 3 derived O-glycans in pancreatic cancer cells suppresses tumor formation and metastasis through modulation of mucins and extracellular matrix proteins glycosylation patterns, as well as down regulation of growth factors and growth factor receptors.

Keywords: Core 3 synthase, β3GnT-6, pancreatic cancer, Tn epitope and MUC1