Increase of O-glycosylated oncofetal fibronectin in high glucose-induced epithelial-mesenchymal transition of cultured human epithelial cells

• Published in: PloS one Vol. 8; no. 4; p. e60471
• Main Authors: Alisson-Silva, Frederico, Freire-de-Lima, Leonardo, Donadio, Joana L, Lucena, Miguel C, Penha, Luciana, Sá-Diniz, Julliana N, Dias, Wagner B, Todeschini, Adriane R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.04.2013; Public Library of Science (PLoS)
• Subjects: Aberration; Amino Acid Sequence; Biology; Biomarkers - metabolism; Biosynthesis; Bone marrow; Bone morphogenetic proteins; Cancer; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell morphology; Cell Movement - drug effects; Cell Shape - drug effects; Cytology; Diabetes; Enzymes; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - drug effects; Extracellular matrix; Fibronectin; Fibronectins; Fibronectins - metabolism; Fructose; Fructose-6-phosphate; Gene expression; Glucose; Glucose - pharmacology; Glucose metabolism; Glutamine; Glycosylation; Glycosylation - drug effects; Hexosamines - biosynthesis; Humans; Hyperglycemia - pathology; Kinases; Markers; Medicine; Mesenchyme; Mesoderm - drug effects; Mesoderm - metabolism; Metabolism; Metastases; Metastasis; Molecular Sequence Data; Motility; mRNA; Nitrogenous Group Transferases - metabolism; Peptides - chemistry; Peptides - pharmacology; Phosphates; Polypeptides; Proteins; Pulmonary fibrosis; RNA; Secretion; Stem cells; Transforming Growth Factor beta1 - pharmacology; Transforming growth factors; Rio de Janeiro Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060471

Growing evidences indicate that aberrant glycosylation can modulate tumor cell invasion and metastasis. The process termed "epithelial-mesenchymal transition" (EMT) provides a basic experimental model to shed light on this complex process. The EMT involves a striking decline in epithelial markers, accompanied by enhanced expression of mesenchymal markers, culminating in cell morphology change and increased cell motility. Few recent studies have established the participation glycosylation during EMT. Studies now come into knowledge brought to light the involvement of a site-specific O-glycosylation in the IIICS domain of human oncofetal fibronectin (onfFN) during the EMT process. Herein we show that high glucose induces EMT in A549 cells as demonstrated by TGF-β secretion, cell morphology changes, increased cellular motility and the emergence of mesenchymal markers. The hyperglycemic conditions increased onfFN protein levels, promoted an up regulation of mRNA levels for ppGalNAc-T6 and FN IIICS domain, which contain the hexapeptide (VTHPGY) required for onfFN biosynthesis. Glucose effect involves hexosamine (HBP) biosynthetic pathway as overexpression of glutamine: fructose-6-phosphate amidotransferase increases mesenchymal markers, onfFN levels and mRNA levels for FN IIICS domain. In summary, our results demonstrate, for the first time that the metabolism of glucose through HBP promotes O-glycosylation of the oncofetal form of FN during EMT modulating tumorogenesis.