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Human-Specific Elimination of Epithelial Siglec-XII Suppresses the Risk of CRC Initiation and Progression [CACO]

ABSTRACT: Human-specific changes in specific Siglecs is one of the reasons put forth as molecular mechanisms that could explain human proneness to developing cancers. The SIGLEC12 gene, which encodes the Siglec-XII protein mainly found on epithelial cells, has a fixed homozygous missense mutation in a critical arginine renders unable to recognize its natural ligand. Additionally, the gene harbors a polymorphic frameshift mutation that eliminates expression of the full-length protein in most humans. We hypothesized that dysfunctional Siglec-XII is involved in cancer progression in humans' epithelia. Here we report that the forced expression of human Siglec-XII in caco-2 cells showed that differentially expressed genes in Siglec-XII cells were enriched for diverse bioenergetic processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262085 | GEO | 2024/03/27

REPOSITORIES: GEO

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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of LPS-TLR4 signalling and one report (Wu et al 2016) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wildtype (WT) and siglec E deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR-4 signalling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing 3 different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and –G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec E dependent alteration in macrophage phenotype that could be relevant to functional responses in host defence. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow derived DCs (BMDC), splenic DCs and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E.coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signalling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

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Human-Specific Elimination of Epithelial Siglec-XII Suppresses the Risk of CRC Initiation and Progression [CACO]

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