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

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 To investigate the impact of the expression of human SIGLEC12 in mouse epithelia, we developed a knock-in mouse model that allows its conditional expression only in the villi and crypts of the small and large intestine (SIGLEC12-Villin1-Cre-ERT). SIGLEC12 knock in mice (SIGLEC12-Villin1-Cre-ERT) and controls (Villin1-Cre-ERT) received 5 days treatment (10 mg/ml) with tamoxifen, to induce SIGLEC12 expression. After 7 days of the last tamoxifen administration mice were sacrificed, colons were harvested. We then performed gene expression profiling analysis using data obtained from RNA-seq of three mice for each condition.