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

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 transgenic conditional expression of human Siglec-XII in mouse intestinal epithelia increased the number and size of cancers in a model of colitis-associated colorectal carcinoma (AOM/DSS). RNA sequencing of the colons at baseline and after AOM/DSS challenge derived a gene signature comprised of the differentially expressed genes (DEGs) between controls (Villin1-Cre-ER(T2)) and Siglec-XII-expressing mice, showing that upregulated DEGs in Siglec-XII mice were enriched for diverse bioenergetic processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE262087 | GEO | 2024/03/27

REPOSITORIES: GEO

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

Project description: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 transgenic conditional expression of human Siglec-XII in mouse intestinal epithelia did not by itself cause carcinomas and RNA sequencing of the colons at baseline derived a gene signature without differentially expressed genes (DEGs) between controls (Villin1-Cre-ER(T2)) and Siglec-XII-expressing mice

2024-03-27 | GSE262086 | GEO

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

Project description: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.

2024-03-27 | GSE262085 | GEO

mRNAs and miRNAs expression data from AOM/DSS, AOM, DSS and control mouse colon epithelial tissue at day100 when tumor formed in AOM/DSS bearing mice --- miRNA microarray

Project description:To find out which miRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed miRNA microarray as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation. 5-7 weeks female BALB/c mice, (1) AOM/DSS group: AOM 12.5mg/kg i.p. at day 1, DSS drinking 5d/21dx3circles from day 5; (2) AOM group: AOM 10mg/kg i.p. 1/weekx6 from day 1; (3) DSS group: DSS drinking 5d/21dx3circles from day 5. The distal colon epithelial tissues were collected at day100 when tumor formed in AOM/DSS bearing mice. The miRNA microarray experiments were performed together.

2013-05-10 | E-GEOD-44983 | biostudies-arrayexpress

mRNAs and miRNAs expression data from AOM/DSS, AOM, DSS and control mouse colon epithelial tissue at day100 when tumor formed in AOM/DSS bearing mice --- mRNA expression data

Project description:To find out which mRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation. 5-7 weeks female BALB/c mice, (1) AOM/DSS group: AOM 12.5mg/kg i.p. at day 1, DSS drinking 5d/21dx3circles from day 5; (2) AOM group: AOM 10mg/kg i.p. 1/weekx6 from day 1; (3) DSS group: DSS drinking 5d/21dx3circles from day 5. The distal colon epithelial tissues were collected at day100 when tumor formed in AOM/DSS bearing mice. The whole genome microarray expression profiling experiments were performed together.

2013-05-10 | E-GEOD-44904 | biostudies-arrayexpress

Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation

Project description:Collagen XII, belonging to the fibril-associated collagens, is a homotrimeric secreted extracellular matrix (ECM) protein encoded by the COL12A1 gene. Mutations in the human COL12A1 gene cause an Ehlers-Danlos/myopathy overlap syndrome leading to skeletal abnormalities and muscle weakness. Here, we studied the role of collagen XII in joint pathophysiology by analyzing collagen XII deficient mice and human patients. We found that collagen XII is widely expressed across multiple connective tissue of the developing joint. Lack of collagen XII in mice destabilizes tendons and the femoral trochlear groove to induce patellar subluxation in the patellofemoral joint. These changes are associated with an ECM damage response in tendon and secondary quadriceps muscle degeneration. Moreover, patellar subluxation was also identified as a clinical feature of human patients with collagen XII deficiency. The results provide an explanation for joint hyperlaxity in mice and human patients with collagen XII deficiency.

2023-06-19 | GSE234964 | GEO

Self-associated molecular patterns mediate cancer immune evasion by engagement of Siglec receptors

Project description:Cancer immunotherapy targeting inhibitory receptors on T cells has changed the landscape of oncological practice, but most patients do not respond to current approaches. Thus, new targets on T cells for cancer immunotherapy are needed. CD33-related Siglecs are pattern recognition immune receptors binding to a broad range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) to dampen unwanted immune responses against self. Naïve T cells in humans have very low levels of inhibitory Siglec expression. Here, we show Siglec-9 in non-small cell lung cancer (NSCLC) are significantly upregulated on tumor-infiltrating T cells. These findings were confirmed in other tumor types including colorectal cancer, and ovarian cancer. Characterization of Siglec-9 expressing T cells showed a co-expression of inhibitory receptors including PD-1 and a distinct phenotype with increased cytokine production upon restimulation, compared to Siglec negative T cells. Functional analysis by reduction of sialoglycan-SAMPs on tumor cells in vitro and in vivo demonstrated an increased tumor cell killing and an inhibition of tumor growth. Overexpression of inhibitory Siglecs on T cells enhanced tumor growth in mice and exchange of inhibitory Siglecs on mouse T cells with an activating Siglec enhanced anti-cancer immunity. Increased T cell expression of Siglec-9 in NSCLC patients also correlated with survival, and analysis of Siglec-9 polymorphisms showed an association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as potential new target to improve T cell activation and cancer immunotherapy.

2018-12-26 | GSE115305 | GEO

GENCODE PCR-Seq Batch XII

Project description:GENCODE PCR-Seq Batch XII

| PRJEB7862 | ENA

mRNAs and miRNAs expression data from AOM/DSS, AOM, DSS and control mouse colon epithelial tissue at day100 when tumor formed in AOM/DSS bearing mice --- miRNA microarray

2013-05-10 | GSE44983 | GEO

mRNAs and miRNAs expression data from AOM/DSS, AOM, DSS and control mouse colon epithelial tissue at day100 when tumor formed in AOM/DSS bearing mice --- mRNA expression data

2013-05-10 | GSE44904 | GEO

GENCODE PCR-Seq Batch XII

Project description:As part of the ENCODE consortium the GENCODE project is producing a reference gene set through manual and automated gene prediction. Selected transcript models are verified experimentally by RT-PCR amplification of at least one of their unique splice junctions followed by sequencing. The experiment targets are manually annotated transcripts with novel or putative status, non-pseudogene biotype and unique splice junctions not validated previously. For Batch XII 416 splice junctions from GENCODE15 (released January 2013) were chosen for experimental verification.

2014-11-26 | E-MTAB-3122 | biostudies-arrayexpress

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