Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

Abstract

The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is downregulated in colonic and intestinal hyperplastic lesions as well as in other cancers, where it functions as a tumor suppressor. To investigate the functions of CEACAM1 in the normal intestine and in intestinal tumors, we generated a compound knockout mouse model and examined both Ceacam1 À/À and Apc 1638N/ þ :Ceacam1 À/À mice. Ceacam1 À/À intestinal cells exhibited a significant decrease in apoptosis, with no change in proliferation or migration, however. Compound Apc 1638N/ þ :Ceacam1 À/À mice demonstrated an increase in intestinal tumor multiplicity and tumor progression. Increases in intussusceptions and desmoid lesions were also observed. We have shown that CEACAM1-L associates with b-catenin by co-immunoprecipitation and colocalization in CEACAM1-L-transfected CT26 and CT51 mouse colon carcinoma cells. Ceacam1 À/À enterocytes displayed decreased glycogen synthase kinase 3-b activity with corresponding nuclear localization of b-catenin. Increased T-cell factor/Lef transcriptional activity was observed in CEACAM1-null CT51 colonic cells and in Caco2 colon cancer cells in which CEACAM1 was downregulated. A significant increased expression in c-Myc and cyclin D1 targets of the Wnt signaling pathway was also revealed in the Ceacam1 À/À intestine. CEACAM1 therefore actively participates in Wnt signaling in intestinal cells and its downregulation in intestinal tissue contributes to malignancy by augmenting tumor multiplicity and progression.

MiniSOX9, a dominant-negative variant in colon cancer cells

“…How MiniSOX9, devoid of transactivation domain, can activate Wnt? It might be a consequence of SOX9 inhibition, because SOX9 upregulates ICAT (inhibitor of b-catenin and T-cell factor (TCF))/TCF interaction (Tago et al, 2000) and the Groucho-related corepressors TLE2-4 (Cavallo et al, 1998;Roose et al, 1998) in HT29Cl.16E cells (Bastide et al, 2007), as well as CEACAM1 , which binds to the armadillo repeats of b-catenin, thereby inducing its redistribution from the cytosol to the plasma membrane (Jin et al, 2008;Leung et al, 2008). Moreover, MiniSOX9 is able to activate the Wnt pathway on its own, through its capacity to bind to b-catenin and inducing b-catenin accumulation in the nucleus.…”

A new mechanism of SOX9 action to regulate PKCα expression in the intestine epithelium

“…the binding of SOX9 to DNA (Bastide et al, 2007). This inhibition might result from an upregulation of groucho-related inhibitors of the β-catenin-Tcf complex (Bastide et al, 2007) and of CEACAM1, a direct SOX9 target (Jin et al, 2008;Leung et al, 2008;Zalzali et al, 2008). Indeed, the W143R SOX9 mutant, which is unable to bind DNA, is unable to inhibit the Wnt-APC pathway, although it is able to repress PKCα expression, as shown in the present study.…”

CEACAM1 Expression in Oligodendrocytes of the Developing Rat Brain Shows a Spatiotemporal Relation to Myelination and Is Altered in a Model of Encephalopathy of Prematurity

“…Some of the cascades important in myelination are of special interest as an interference of CEACAM1 with these signaling cascades is known. For example, Wnt signaling is a candidate signaling pathway that may be altered by CEACAM1 as Wnt signaling is involved in myelination [51,52,53], and CEACAM1-L directly interacts with β-catenin, a key molecule in Wnt signaling [19,54]. Another important signaling in myelination is TLR2 signaling, as TLR2 is expressed in oligodendrocytes [55], stimulation of TLR2 inhibits oligodendrocyte maturation and myelination [56], and CEACAM1 interacts with TLR2 signaling [17].…”