Expression of the Clustered NeuAcα2–3Galβ O-Glycan Determines the Cell Differentiation State of the Cells

Human embryonic stem cells (hESCs) are pluripotent stem cells from early embryos, and their self-renewal capacity depends on the sustained expression of hESC-specific molecules and the suppressed expression of differentiation-associated genes. To discover novel molecules expressed on hESCs, we gener...

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Published in:The Journal of biological chemistry 2014-09, Vol.289 (37), p.25833-25843
Main Authors: Higashi, Kiyoshi, Asano, Kouji, Yagi, Masaki, Yamada, Keita, Arakawa, Tatsuhiko, Ehashi, Tomo, Mori, Takashi, Sumida, Kayo, Kushida, Masahiko, Ando, Satoshi, Kinoshita, Mitsuhiro, Kakehi, Kazuaki, Tachibana, Taro, Saito, Koichi
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - genetics
Calcium-Binding Proteins
Cell Biology
Cell Differentiation - genetics
Cell Differentiation - immunology
DNA-Binding Proteins
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Endothelial Cells - metabolism
Epitopes - immunology
Fibroblasts - metabolism
Flow Cytometry
Gene Expression Regulation, Developmental - immunology
Humans
Keratinocytes - metabolism
Neoplastic Stem Cells - immunology
Neoplastic Stem Cells - metabolism
Oligonucleotide Array Sequence Analysis
Oligosaccharides - genetics
Oligosaccharides - immunology
Receptors, Cell Surface - genetics
Receptors, Cell Surface - immunology
Stomach Neoplasms - genetics
Stomach Neoplasms - immunology
Stomach Neoplasms - pathology
Tumor Suppressor Proteins
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Summary:Human embryonic stem cells (hESCs) are pluripotent stem cells from early embryos, and their self-renewal capacity depends on the sustained expression of hESC-specific molecules and the suppressed expression of differentiation-associated genes. To discover novel molecules expressed on hESCs, we generated a panel of monoclonal antibodies against undifferentiated hESCs and evaluated their ability to mark cancer cells, as well as hESCs. MAb7 recognized undifferentiated hESCs and showed a diffuse band with molecular mass of >239 kDa in the lysates of hESCs. Although some amniotic epithelial cells expressed MAb7 antigen, its expression was barely detected in normal human keratinocytes, fibroblasts, or endothelial cells. The expression of MAb7 antigen was observed only in pancreatic and gastric cancer cells, and its levels were elevated in metastatic and poorly differentiated cancer cell lines. Analyses of MAb7 antigen suggested that the clustered NeuAcα2–3Galβ O-linked oligosaccharides on DMBT1 (deleted in malignant brain tumors 1) were critical for MAb7 binding in cancer cells. Although features of MAb7 epitope were similar with those of TRA-1–60, distribution of MAb7 antigen in cancer cells was different from that of TRA-1–60 antigen. Exposure of a histone deacetylase inhibitor to differentiated gastric cancer MKN74 cells evoked the expression of MAb7 antigen, whereas DMBT1 expression remained unchanged. Cell sorting followed by DNA microarray analyses identified the down-regulated genes responsible for the biosynthesis of MAb7 antigen in MKN74 cells. In addition, treatment of metastatic pancreatic cancer cells with MAb7 significantly abrogated the adhesion to endothelial cells. These results raised the possibility that MAb7 epitope is a novel marker for undifferentiated cells such as hESCs and cancer stem-like cells and plays a possible role in the undifferentiated cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.550848