title: Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells.
abstract: The galactoside-binding protein galectin-3 is increasingly recognized as an important player in cancer development, progression, and metastasis via its interactions with various galactoside-terminated glycans. We have shown previously that circulating galectin-3, which is increased up to 30-fold in cancer patients, promotes blood-borne metastasis in an animal cancer model. This effect is partly attributable to the interaction of galectin-3 with unknown receptor(s) on vascular endothelial cells and causes endothelial secretion of several metastasis-promoting cytokines. Here we sought to identify the galectin-3-binding molecule(s) on the endothelial cell surface responsible for the galectin-3-mediated cytokine secretion. Using two different galectin-3 affinity purification processes, we extracted four cell membrane glycoproteins, CD146/melanoma cell adhesion molecule (MCAM)/MUC18, CD31/platelet endothelial cell adhesion molecule-1 (PECAM-1), CD144/VE-cadherin, and CD106/Endoglin, from vascular endothelial cells. CD146 was the major galectin-3-binding ligand and strongly co-localized with galectin-3 on endothelial cell surfaces treated with exogenous galectin-3. Moreover, galectin-3 bound toN-linked glycans on CD146 and induced CD146 dimerization and subsequent activation of AKT signaling. siRNA-mediated suppression of CD146 expression completely abolished the galectin-3-induced secretion of IL-6 and G-CSF cytokines from the endothelial cells. Thus, CD146/MCAM is the functional galectin-3-binding ligand on endothelial cell surfaces responsible for galectin-3-induced secretion of metastasis-promoting cytokines. We conclude that CD146/MCAM interactions with circulating galectin-3 may have an important influence on cancer progression and metastasis.
authors.affiliation: Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE.
authors.forename: Florent
authors.initials: F
authors.lastname: Colomb
authors.affiliation: Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE.
authors.forename: Weikun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Simpson
authors.affiliation: Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE.
authors.forename: Mudaser
authors.initials: M
authors.lastname: Zafar
authors.affiliation: Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Beynon
authors.affiliation: Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Rhodes
authors.affiliation: Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE. Electronic address: lgyu@liv.ac.uk.
authors.forename: Lu-Gang
authors.initials: LG
authors.lastname: Yu
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001798:Blood Proteins; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D001798:Blood Proteins; D051929:CD146 Antigen; D015820:Cadherins; D037502:Galectin 3; D037161:Galectins; D016179:Granulocyte Colony-Stimulating Factor; D015850:Interleukin-6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5; C508600:IL6 protein, human; C428445:LGALS3 protein, human; C497902:MCAM protein, human
keywords: CD146; IL-6; MCAM; carbohydrate-binding protein; cytokine; endothelium; galectin; galectin-3