Reduced Susceptibility to Colitis-Associated Colon Carcinogenesis in Mice Lacking Plasma Membrane-Associated Sialidase

Abstract

Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and change their conformation, intermolecular interactions, and/or half-life. Thus, sialidases are believed to modulate the function of sialoglycoconjugates by desialylation. We previously reported that the membrane-associated mammalian sialidase NEU3, which preferentially acts on gangliosides, is involved in cell differentiation, motility, and tumorigenesis. The NEU3 gene expression is aberrantly elevated in several human cancers, including colon, renal, prostate, and ovarian cancers. The small interfering RNA-mediated knock-down of NEU3 in cancer cell lines, but not in normal cell-derived primary cultures, downregulates EGFR signaling and induces apoptosis. Here, to investigate the physiological role of NEU3 in tumorigenesis, we established Neu3-deficient mice and then subjected them to carcinogen-induced tumorigenesis, using a sporadic and a colitis-associated colon cancer models. The Neu3-deficient mice showed no conspicuous accumulation of gangliosides in the brain or colon mucosa, or overt abnormalities in their growth, development, behavior, or fertility. In dimethylhydrazine-induced colon carcinogenesis, there were no differences in the incidence or growth of tumors between the Neu3-deficient and wild-type mice. On the other hand, the Neu3-deficient mice were less susceptible than wild-type mice to the colitis-associated colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. These results suggest that NEU3 plays an important role in inflammation-dependent tumor development.

Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides

“…Both enzymes have been proposed to play a role in neuronal differentiation based on the results of in vitro experiments (29–31); however, no evidence of this has been obtained in vivo . Neu3‐ and Neu4‐KO mice do not show signs of impaired brain function and have normal behavior and memory (14, 32). Considering the similar substrate specificity of Neu3 and Neu4 (33) and changes in their expression levels in the single‐KO mice demonstrated in this study, it is likely that the enzymes compensate for each other's deficiency, which would explain the lack of neurologic phenotypes in single‐KO models.…”

Glycans and the platelet life cycle

“…Interestingly, silencing of Neu3 in K562 triggers megakaryocytic differentiation of K562 cells. High expression of Neu3 in cancer cells has also been associated with protection against apoptosis in tumor cells [49, 65, 66]. More data are needed to establish if glycan degradation in vivo (i.e., sialic acid loss) triggers the intrinsic apoptotic machinery in platelets, linking glycan degradation and intrinsic apoptotic machinery in the clearance mechanisms regulating platelet survival.…”

Ganglioside Intake Increases Plasma Ganglioside Content in Human Participants

“…Disorders of ganglioside metabolism that do not manifest as diagnosed gangliosidoses 17 may influence development of IBD in Ashkenazi Jews and in other populations. Colitis‐associated carcinogenesis is also linked to aberration in ganglioside metabolism 18 . Since individuals with IBD are at higher risk of developing colorectal cancer, discerning the role of ganglioside metabolism in gut health is of interest.…”