Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems

• Published in: PloS one Vol. 5; no. 9; p. e13002
• Main Authors: Maupin, Kevin A, Sinha, Arkadeep, Eugster, Emily, Miller, Jeremy, Ross, Julianna, Paulino, Vincent, Keshamouni, Venkateshwar G, Tran, Nhan, Berens, Michael, Webb, Craig, Haab, Brian B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.09.2010; Public Library of Science (PLoS)
• Subjects: Analysis; Biosynthesis; Cancer; Carbohydrates; Cell adhesion & migration; Cell Biology/Gene Expression; Cell differentiation; Cell Line, Tumor; Cell surface; Data processing; Differentiation (biology); Drug resistance; Epithelial-Mesenchymal Transition; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetics and Genomics/Cancer Genetics; Genetics and Genomics/Gene Discovery; Genetics and Genomics/Gene Expression; Genomics; Glycan; Glycosaminoglycans; Glycosylation; Humans; Ligands; Lymphoma; Mannose; Mannose receptors; Mesenchyme; Metastasis; Models, Biological; Molecular Biology/Post-Translational Regulation of Gene Expression; Mutation; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - physiopathology; Physiological aspects; Polypeptides; Polysaccharides - genetics; Polysaccharides - metabolism; Proteins; Proteins - genetics; Proteins - metabolism; Proteoglycans; Receptors; Stem cells; Sugar; Sulfation; Target detection; Transforming growth factors; Tumor cell lines; United States > US; Arizona; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013002

The ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT) may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT. As a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1) TGFβ-induced EMT, which provided a look at the active transition between states; 2) a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively) but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining. Alterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific sialylated structures. These results provide leads for targeting aggressive and drug resistant forms of pancreatic cancer cells.