O-glycosylation of MUC1 mucin in prostate cancer and the effects of its expression on tumor growth in a prostate cancer xenograft model

Abstract

MUC1 mucin is up-regulated and aberrantly glycosylated in many human epithelial carcinomas. Over-expression of MUC1 has also been implicated in prostate cancer, but neither the role of MUC1 in the cancer progression nor the mucin O-glycosylation has been fully elucidated. In this study, we characterized the O-glycans on MUC1 when over-expressed in the human prostate cancer cell line C4-2B(4). We found that the main O-glycan consisted of the neutral core 2 oligosaccharide Galβ3(Galβ3/4GlcNAcβ6)GalNAc-ol, with minor components being fucosylated and sialylated variants of the same core 2 oligosaccharide. Small amounts of the shorter core 1 O-glycans were also detected.We then used the MUC1 over-expressing cell lines to study the effects of MUC1 on prostate cancer cell behavior. The results demonstrate that over-expression of MUC1 did not affect the cells' proliferation, but led to a decreased adhesion to the extracellular matrix components fibronectin and collagen I in vitro. When inoculated in BALB/c nude mice, C4-2B(4) cells expressing MUC1 showed a tendency to form fewer tumors than wt cells and the tumors also grew more slowly, but there was a large variation between different tumors. These findings suggest that MUC1 may not have the same cancer-promoting effect in prostate cancer cells that is commonly seen in other epithelial cancers such as breast, colon, and pancreatic cancer.

Glycosylation potential of human prostate cancer cell lines

“…PC-3 and DU145 cells are expected to have only core 1-based O-glycans and appear to be restricted in their ability to form branched chains since the activity of C2GnT1 was undetectable in spite of mRNA expression. In contrast, LNCaP cells are capable of synthesizing a multitude of O-glycan structures with core 1 and 2 structures [51]. …”

MUC1 Expression by Immunohistochemistry Is Associated with Adverse Pathologic Features in Prostate Cancer: A Multi-Institutional Study

“…The mucin family encompasses a diverse set of high molecular weight glycoproteins characterized by the presence of O-linked oligosaccharides to serine or threonine residues [3, 4]. MUC1 protein expression has been found to be significantly elevated in several cancers including CaP [4, 5] and is usually accompanied by altered glycosylation [6, 7]. In addition, MUC1 expression in cancer is usually characterized by a diffuse cytoplasmic staining pattern compared to apically restricted expression typically found in normal tissues [8–11].…”

“…In addition, MUC1 expression in cancer is usually characterized by a diffuse cytoplasmic staining pattern compared to apically restricted expression typically found in normal tissues [8–11]. MUC1 over-expression has been reported to allow malignant cells to evade host immunological defenses and to promote metastasis through a loss of cell–cell and cell–extracellular matrix contact [7, 12–16]. …”

Construction of a Natural Mucin Microarray and Interrogation for Biologically Relevant Glyco-Epitopes

“…[13][14][15][16][17] Eight core structures have been described for mucin-type oligosaccharides (Table S- sialic acids (Neu) and/or sulfate groups. 1,5,18 The combination of different core structures, chain elongation, branching, linkages and the variety of peripheral and terminal residues results in a high degree of mucin oligosaccharide heterogeneity, 1 with dozens to hundreds of diverse oligosaccharides densely substituting the mucin protein backbone 19 in a 'bottle-brush' configuration 20 ( Figure 1A).…”