Depletion of β1,6- N -acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells
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Maar, Hanna
Beimdiek, Julia
Chambers, Samuel
Riecken, Kristoffer
von Itzstein, Mark
Buettner, Falk FR
Everest-Dass, Arun
Lange, Tobias
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Abstract
The commonly altered glycosylation of tumor cells is a hallmark of tumor progression and metastasis formation. One prominent example is the interaction of sialylated glycans at the tumor cell surface with endothelial (E)-selectin as an early event of an adhesion cascade that enables extravasation of circulating tumor cells (CTCs) into distant tissues. In a previous study, we identified GCNT3 (mucin-type core2/ core4 β1,6- N -acetylglucosaminyltransferase) highly over-expressed in gastrointestinal adenocarcinoma cells that facilitate the canonical E-selectin ligands sialyl-Lewis A and X (sLeA/X) for E-selectin binding and endothelial adhesion. Here we show that shRNA-mediated, stable depletion of GCNT3 reduced sLeA (tumor marker CA19-9) presentation on two out of three tested human gastrointestinal adenocarcinoma cell lines, concurrently showing reduced static E-selectin binding. Significant effects of GCNT3 depletion on dynamic, shear-resistant tumor cell adhesion on immobilized E-selectin as well as endothelial cells were only partially and inconsistently observable as were effects on tumor cell proliferation (2D) or 3D colony formation. Nevertheless, tumor cell migration was consistently reduced upon GCNT3 depletion in all tested cell lines. Detailed glycome analyses revealed that GCNT3 depletion caused cell line-specific alterations in N - and O -glycans as well as glycosphingolipids, collectively mainly associating with decreased Core-2 structures resulting in varied abundance of sialylation and Lewis antigen with consistent phenotypic changes. Distinctive N - and O -glycosylation features were found to be inherent to specific cell types. These findings suggest GCNT3 products as possible carriers of sLeA and static E-selectin binding sites as well as common pro-migratory glycans in human gastrointestinal cancer.
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Neoplasia
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59
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© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Clinical sciences
Oncology and carcinogenesis
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Staffeldt, L; Maar, H; Beimdiek, J; Chambers, S; Riecken, K; von Itzstein, M; Buettner, FFR; Everest-Dass, A; Lange, T, Depletion of β1,6- N -acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells, Neoplasia, 2025, 59, pp. 101083