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L1CAM from human melanoma carries a novel type of N-glycan with Gal{Beta}1-4Gal{Beta}1- motif. Involvement of N-linked glycans in migratory and invasive behaviour of melanoma cells.

Significance Statement

L1CAM is expressed in primary melanomas and cutaneous metastases and not in melanocytic nevi and melanocytes. This fact suggests a role for L1CAM in tumor progression. The L1CAM restricted distribution makes this molecule as an ideal target for tumor therapy. We defined a novel N-glycan structure containing sialylated Gal{Beta}1-4Gal{Beta}1-4GlcNAc sequence on the 3-arm antenna of monoantennary complex-type glycan: A1[3]G(4)2. This result was surprising, because nothing is presently known about the possible expression of Gal{Beta}1-4Gal{Beta}1-4GlcNAc sequence on either glycoproteins or glycolipids in man or other mammals. To our knowledge, identified by us A1[3]G(4)2 structure [Gal{Beta}1-4Gal{Beta}1-4GlcNAc{Beta}1-2Man{Alpha}1-3(Man{Alpha}1-6)Man{Beta}1-4GlcNAc{Beta}1GlcNAc] of L1CAM acetylated on sialic acid is the first cancer biomarker related to metabolic replacement of Neu5Ac with the immunogenic dietary NeuGc molecule in protein-linked N-glycans. The coexistence of acetylated N-glycolylneuraminic acid with Gal{Beta}1-4Gal{Beta}1-4GlcNAc sequence in A1[3]G(4)2 structure generated a novel, unique neo-tumour-associated xenoautoantigen in human melanoma. Since cancer cells shed the L1CAM ectodomain into circulation, the Gal{Beta}1-4Gal{Beta}1-4 autoantigen potentially gives us a novel serum biomarker for early detection of melanoma.

L1CAM from human melanoma carries a novel type of N-glycan with Gal{Beta}1-4Gal{Beta}1- motif. Involvement of N-linked glycans in migratory and invasive behaviour of melanoma cells.. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Journal Reference

Hoja-Łukowicz D, Link-Lenczowski P, Carpentieri A, Amoresano A, Pocheć E, Artemenko KA, Bergquist J, Lityńska A. Glycoconj J. 2013 Apr;30(3):205-25.

Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, Krakow, Poland. [email protected]

Abstract

Dramatic changes in glycan biosynthesis during oncogenic transformation result in the emergence of marker glycans on the cell surface. We analysed the N-linked glycans of L1CAM from different stages of melanoma progression, using high-performance liquid chromatography combined with exoglycosidase sequencing, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, and lectin probes. L1CAM oligosaccharides are heavily sialylated, mainly digalactosylated, biantennary complex-type structures with galactose {Beta}1-4/3-linked to GlcNAc and with or without fucose {Alpha}1-3/6-linked to GlcNAc. Hybrid, bisected hybrid, bisected triantennary and tetraantennary complex oligosaccharides, and {Beta}1-6-branched complex-type glycans with or without lactosamine extensions are expresses at lower abundance. We found that metastatic L1CAM possesses only {Alpha}2-6-linked sialic acid and the loss of {Alpha}2-3-linked sialic acid in L1CAM is a phenomenon observed during the transition of melanoma cells from VGP to a metastatic stage. Unexpectedly, we found a novel monoantennary complex-type oligosaccharide with a Gal{Beta}1-4Gal{Beta}1- epitope capped with sialic acid residues A1[3]G(4)2S2-3. To our knowledge this is the first report documenting the presence of this oligosaccharide in human cancer. The novel and unique N-glycan should be recognised as a new class of human melanoma marker. In functional tests we demonstrated that the presence of cell surface {Alpha}2-3-linked sialic acid facilitates the migratory behaviour and increases the invasiveness of primary melanoma cells, and it enhances the motility of metastatic cells. The presence of cell surface {Alpha}2-6-linked sialic acid enhances the invasive potential of both primary and metastatic melanoma cells. Complex-type oligosaccharides in L1CAM enhance the invasiveness of metastatic melanoma cells.

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