Abstract
Mucin-type O-glycosylation plays a crucial role in several physiological and pathological processes of the gastric tissue. Modifications in enzymes responsible for key glycosylation steps and the consequent abnormal biosynthesis and expression of their glycan products constitute well-established molecular hallmarks of disease state. This review addresses the major role played by mucins and associated O-glycan structures in Helicobacter pylori adhesion to the gastric mucosa and the subsequent establishment of a chronic infection, with concomitant drastic alterations of the gastric epithelium glycophenotype. Furthermore, alterations of mucin expression pattern and glycan signatures occurring in preneoplastic lesions and in gastric carcinoma are also described, as well as their impact throughout the gastric carcinogenesis cascade and in cancer progression. Altogether, mucin-type O-glycosylation alterations may represent promising biomarkers with potential screening and prognostic applications, as well as predictors of cancer patients’ response to therapy.
Highlights
Gastric carcinogenesis is a sequential multistep process that encompasses molecular, genetic and histologic alterations, leading to the development of gastric cancer (GC) (Figure 1) [1].Intestinal type GC constitutes a complex multifactorial pathway resulting from the interplay of environmental risk factors, infection with Helicobacter pylori (H. pylori) bacterium, classified as a type I human carcinogen [2], and host genetic susceptibility [1,3].Biomolecules 2016, 6, 33; doi:10.3390/biom6030033 www.mdpi.com/journal/biomoleculesBiomolecules 2016, 6, 33 cells with neutral mucin expression are gradually replaced by acidic sialomucin‐producing cells with an intestinal phenotype [1]
Based on the critical role that glycans play in the adhesion of H. pylori to the gastric epithelium and the establishment of a chronic infection, different strategies aiming the blockage of the glycan-mediated adhesion have been proposed
The complete type, or type I, is characterized by a clear loss of expression of the mucins MUC1, MUC5AC, and MUC6, which are normally present in the gastric mucosa, and aberrant expression of the intestinal MUC2 mucin in goblet cells (Figure 1bI)
Summary
Gastric carcinogenesis is a sequential multistep process that encompasses molecular, genetic and histologic alterations, leading to the development of gastric cancer (GC) (Figure 1) [1]. The development of intestinal metaplasia (IM) originates multiple foci where superficial foveolar cells with neutral mucin expression are gradually replaced by acidic sialomucin-producing cells with an intestinal phenotype [1] This precancerous lesion is associated with an increased risk of GC development. It has been shown that the abnormal expression of enzymes controlling key glycosylation steps, or alterations of their glycan products, have a clear association with GC onset and progression, through their implication in several features of tumour cell biology and behaviour [5] These glycan alterations occurring during the gastric carcinogenic pathway include increased expression of sialylated terminal structures, as well as aberrant expression of simple-mucin-type carbohydrate antigens. Glycans represent well-established key mediators of different aspects of tumour progression, regulating several processes, such as proliferation, invasion, metastasis and angiogenesis [6]
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