Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer

Abstract

Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-β (TGF-β). TGF-β bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely, N-glycans, O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-β signaling components regulates TGF-β secretion, bioavailability and TGF-β receptor function. Then, we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-β signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.

Posttranslational Modifications of Smurfs: Emerging Regulation in Cancer

“…Therefore, we think that in different cancer types, due to low protein levels of Smurf1/2 and/or deficiency of external stimulus of upstream factors, it makes it difficult to detect vivo Smurf modifications ( 39 , 49 ). Meantime, modification events in vivo could be affected by cytokines released from other types of tissues ( 102 ). Nonetheless, vitro experiments of cancer cells can also reflect modification events occurring in normal and cancer tissues to a great extent ( 96 ).…”

Analysis of Serum Paraoxonase 1 Using Mass Spectrometry and Lectin Immunoassay in Patients With Alpha-Fetoprotein Negative Hepatocellular Carcinoma

“…In addition, traditional lectin ELISA was conducted for each patient of another 56 patients for further confirmation. For the validation phase, an independent cohort including 32 patients with LC and 32 with AFP-negative HCC were assessed individually by 16 O/ 18 O C-terminal labeling quantitation method after IP, which were entirely separated from discovery set samples. Serum samples were stored at −80°C and handled identically.…”

“…Immobilized trypsin (Thermo Scientific, Rockford, IL) was added and dried with a vacuum centrifuge. H 2 16 O/H 2 18 O (97%, Cambridge Isotope Laboratories, Andover, MA) was added respectively for 24 h at the temperature of 37°C. 16 Oand 18 O-labeled digests were pooled by equal volumes before mass spectrometry analysis.…”

“…H 2 16 O/H 2 18 O (97%, Cambridge Isotope Laboratories, Andover, MA) was added respectively for 24 h at the temperature of 37°C. 16 Oand 18 O-labeled digests were pooled by equal volumes before mass spectrometry analysis. The 16 O/ 18 O labeled Nglycopeptides were identified and quantified according to a previous study (22).…”

“…In humans, nearly 70% of proteins are glycosylated (13). Moreover, Nglycosylation regulates the correct folding, transport, and biological function of various proteins (14) and has been shown to be involved in cancer, inflammatory diseases, and autoimmune diseases by participating in proliferation, cellmatrix interactions, migration, and differentiation (15,16). Glycosylation has been reported to be associated with most cancer serum biomarkers (17).…”