Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei

Area of Science:

• Oncology
• Glycomics
• Biochemistry

Background:

• Pseudomyxoma peritonei (PMP) is a rare mucinous adenocarcinoma, often originating in the appendix, characterized by peritoneal cavity filling with mucinous ascites.
• While KRAS and GNAS mutations are common in PMP, other driver mutations are infrequent, suggesting alternative oncogenic pathways.
• Altered glycosylation is recognized as a factor that can promote carcinogenesis.

Purpose of the Study:

• To investigate the role of altered N-linked glycosylation, particularly fucosylation, in Pseudomyxoma Peritonei (PMP).
• To compare N-linked glycan profiles between PMP tissues and normal appendix samples.
• To identify specific fucosylation-related enzymes and their expression levels in PMP.

Main Methods:

• Mass spectrometry was used to analyze N-linked glycan profiles of eight normal appendix samples and sixteen PMP specimens (eight low-grade, eight high-grade).
• mRNA expression of fucosylation-related enzymes was quantified in PMP tissues and controls.
• Protein expression of specific enzymes was assessed in PMP cells using immunohistochemistry.
• Functional studies involved restoring fucosylation in an adenocarcinoma cell line to observe effects on MUC2 expression.

Main Results:

• Significant differences in N-linked glycan profiles were observed between PMP and normal appendix tissues, with a notable increase in fucosylation in PMP.
• Up-regulated mRNA expression of four fucosylation-related enzymes, including fucosyltransferase 8 and three GDP-fucose biosynthetic enzymes, was found in PMP tissues.
• Up-regulated protein expression of three GDP-fucose biosynthetic enzymes was confirmed in PMP cells.
• Restoration of fucosylation enhanced MUC2 expression in a fucosylation-deficient intestinal adenocarcinoma cell line.

Conclusions:

• Altered glycosylation, specifically increased fucosylation, is closely linked to the characteristic mucin production in Pseudomyxoma Peritonei.
• Fucosylation-related enzymes show altered expression in PMP, contributing to the disease's unique glycomic signature.
• These findings highlight the potential of targeting glycosylation pathways in PMP research and treatment.