Focused glycomic analysis of the N‐linked glycan biosynthetic pathway in ovarian cancer

Abstract

Epithelial ovarian cancer is the deadliest female reproductive tract malignancy in Western countries. Less than 25% of cases are diagnosed when the cancer is confined, however, pointing to the critical need for early diagnostics for ovarian cancer. Identifying the changes that occur in the glycome of ovarian cancer cells may provide an avenue to develop a new generation of potential biomarkers for early detection of this disease. We performed a glycotranscriptomic analysis of endometrioid ovarian carcinoma using human tissue, as well as a newly developed mouse model that mimics this disease. Our results show that the N-linked glycans expressed in both non-diseased mouse and human ovarian tissues are similar; moreover, malignant changes in the expression of N-linked glycans in both mouse and human endometrioid ovarian carcinoma are qualitatively similar. Lectin reactivity was used as a means for rapid validation of glycan structural changes in the carcinomas that were predicted by the glycotranscriptome analysis. Among several changes in glycan expression noted, the increase of bisected N-linked glycans and the transcripts of the enzyme responsible for its biosynthesis, GnT-III, was the most significant. This study provides evidence that glycotranscriptome analysis can be an important tool in identifying potential cancer biomarkers.

Specific Glycosylation of Membrane Proteins in Epithelial Ovarian Cancer Cell Lines: Glycan Structures Reflect Gene Expression and DNA Methylation Status

“…For the first time, we have demonstrated that the expression of bisecting GlcNAc on N-linked glycoproteins is correlated with the expression of the MGAT3 gene that expresses the enzyme that adds this monosaccharide in a ␤ 1-4 linkage to the core of the N-glycans. This is consistent with a previous study using mouse models (n ϭ 9) and human fresh frozen tissue samples (n ϭ 5), in which there was elevated mRNA expression of MGAT3 in endometrioid ovarian cancer in both species types as compared with normal ovaries (51). The authors used the lectin, phytohemeagglutinin E (E-PHA), which has specificity toward binding to bisecting-type N-glycan determinants on glycoproteins.…”

“…The authors used the lectin, phytohemeagglutinin E (E-PHA), which has specificity toward binding to bisecting-type N-glycan determinants on glycoproteins. Positive staining for E-PHA was detected in normal controls and more than 2-fold increase of bisecting GlcNAc was detected in the ovarian cancer tissue samples (51). In our study, however, bisecting GlcNAc was completely absent in both non-cancerous cell lines and comprised up to 13% of the N-glycans in the cancer cells.…”

Epigenetic silencing ofHNF1Aassociates with changes in the composition of the human plasmaN-glycome

“…Total glycome was divided into 16 groups (chromatographic peaks) of sialylated glycans, 13 groups of desialylated glycans, and four groups of differentially charged glycans glycosyltransferases, glycosidases, enzymes for sugar nucleotide biosynthesis, transporters, etc.,) are currently identified. 15,16 The expression of "glyco-genes" and the activity of corresponding enzymes are affected by various transcription factors, Golgi organizers, proton pumps and other proteins, further increasing the number of genes and protein products that are directly or indirectly involved in the synthesis of glycans. The majority of studies on the role of genetic factors on glycosylation are limited to a group of rare congenital disorders of glycosylation 17 and studies on genetics of glycosylation in normal populations.…”

Evaluation of Riproximin Binding Properties Reveals a Novel Mechanism for Cellular Targeting

“…No direct link between the presence of NA2 or NA3 and cancer has been established so far. However, N-glycans from cancer cells show higher branching, resulting in a higher NA3 density (15,36,37) that would provide additional riproximin binding sites. On the other hand, the possibility cannot be excluded that these struc- 50 value is Ͼ1000 g/ml.…”