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CEACAM1

BGP|BGP1|BGPI;carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein);CEACAM1;carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)

CD66a antigen|antigen CD66|carcinoembryonic antigen-related cell adhesion molecule 1

19q13.2

protein-coding

Count: 2; Pubmed_search,Generif

CEACAM1-4L (carcinoembryonic antigen cell adhesion molecule 1, with 4 extracellular Ig-like domains and a long, 71 amino acid cytoplasmic domain) is expressed in epithelial cells and activated T-cells, but is down-regulated in most epithelial cell cancers and T-cell leukemias. A highly conserved sequence within the cytoplasmic domain has ca 50% sequence homology with Tcf-3 and -4, transcription factors that bind beta-catenin, and to a lesser extent (32% homology), with E-cadherin that also binds beta-catenin. We show by quantitative yeast two-hybrid, BIAcore, GST-pull down, and confocal analyses that this domain directly interacts with beta-catenin, and that H-469 and K-470 are key residues that interact with the armadillo repeats of beta-catenin. Jurkat cells transfected with CEACAM1-4L have 2-fold less activity in the TOPFLASH reporter assay, and in MCF7 breast cancer cells that fail to express CEACAM1, transfection with CEACAM1 and growth in Ca2+ media causes redistribution of beta-catenin from the cytoplasm to the cell membrane, demonstrating a functional role for the long cytoplasmic domain of CEACAM1 in regulation of beta-catenin activity.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), an adhesion molecule of the immunoglobulin superfamily, has been characterized as a putative tumor suppressor because it is frequently down-regulated in aggressive types of cancer cells. Recently, however, several studies have shown that CEACAM1 actively contributes to malignant progression or migration in some types of tumor cells, suggesting that the role of CEACAM1 might be diverse among different types of cancer cells. To investigate the functional consequences of CEACAM1 expression in hepatocellular carcinoma, we analyzed the status of CEACAM1 in hepatoma cell lines HLF, PLC/PRF/5, HepG2 and KYN-2. We found that CEACAM1 was only expressed in HepG2 cells, which show a unique property for enhanced anchorage-independent growth. When HepG2 cells were treated with small interfering RNA targeted against CEACAM1, the growth rate in monolayer culture was increased. In contrast, when HepG2 cells were cultured in suspension, inhibition of CEACAM1 expression significantly decreased the growth rate, and the speed of cell-cell attachment was repressed. Hyaluronidase treatment attenuated the growth rate of HepG2 cells in suspension culture, indicating that cell-cell attachment is a requisite for anchorage-independent growth. Our data may reveal the dual role of CEACAM1 on hepatocarcinogenesis, by showing that CEACAM1 acts as a tumor suppressor in HepG2 cells in anchorage-dependent growth conditions, while in anchorage-independent growth conditions, it augments cell proliferation by potentiating the cell-cell attachment.

Defects in the adenomatous polyposis coli (APC) tumor suppressor pathway are sufficient for neoplastic transformation as the initiating step in colorectal carcinogenesis. In contrast, hyperplastic tumors possess normal APC function, and it is unclear whether they represent significant precursor lesion in cancer development. CEACAM1 is a tumor suppressor whose expression is known to be lost in the great majority of early adenomas and carcinomas. We found that loss of CEACAM1 expression is more common in neoplastic tumors than APC mutations. While APC function was normal in hyperplastic aberrant cypt foci and hyperplastic polyps, loss of CEACAM1 was observed as frequently as in the neoplasias. Moreover, the presence or absence of CEACAM1 expression in the hyperplastic tumors correlates with normal or reduced apoptosis, respectively. In vitro, CEACAM1 acts as a regulator of apoptosis in CEACAM1-transfected Jurkat cells. Finally, in human HT29 colon cancer cells, apoptosis can be specifically restored by induction of CEACAM1 expression. These data suggest an oncodevelopmental link between neoplasia and hyperplasia and demonstrate that CEACAM1 acts as a regulator of apoptosis in the colonic epithelium. Thus, failure of the maturing colon cell to express CEACAM1 is likely to contribute to the development of hyperplastic lesions, which may eventually pave the way to neoplastic transformation and colon cancer development.

We have previously shown that CEACAM1, a cell-adhesion molecule, acts as a tumor suppressor in prostate carcinoma. expression of CEACAM1 in prostate cancer cells suppresses their growth in vivo. However, CEACAM1 has no effect on the growth of prostate cancer cells in vitro. This difference suggests that the antitumor effect of CEACAM1 may be due to inhibition of tumor angiogenesis, perhaps by increased secretion of antiangiogenic molecules from the cells. In this study, we have demonstrated that expression of CEACAM1 in DU145 prostate cancer cells induced the production of a factor or factors that specifically blocked the growth of endothelial but not epithelial cells. Conditioned medium from the CEACAM1-expressing cells but not control luciferase-expressing cells inhibited endothelial cell migration up a gradient of stimulatory vascular endothelial growth factor in vitro and inhibited corneal neovascularization induced by basic fibroblast growth factor in vivo. Moreover, conditioned medium from CEACAM1-expressing cells induced endothelial cell apoptosis in vitro. Only medium conditioned by CEACAM1 mutants that were able to suppress tumor growth in vivo could cause endothelial cell apoptosis. These observations suggest that CEACAM1-mediated tumor suppression in vivo is, at least in part, due to the ability of CEACAM1 to inhibit tumor angiogenesis.

Previous studies have shown that the expression of the cell-cell adhesion molecule (C-CAM1), located at chromosome 19, is down-regulated in several types of human cancers, including prostate and breast cancers. Two major isoforms of C-CAM1, the long or L-form C-CAM1 and the short or S-form C-CAM1, are derived from the C-CAM1 gene through alternative splicing. Tumor cells transfected with L-form C-CAM1, which contains a cytoplasmic domain, display significantly lower growth rates and less tumorigenicity in both in vitro and in vivo models compared with untransfected tumor cells, suggesting that L-form C-CAM1 may be a tumor suppressor. The transfection of the cytoplasmic domain of L-form C-CAM1 could also cause suppression of tumor growth, further supporting the role of L-form C-CAM1 in tumorigenesis. In contrast to reports of most of the tumor types tested, Ohwada et al. (Am. J. Respir. Cell Mol. Biol., 11: 214-220, 1994) reported that C-CAM1 was not down-regulated or even up-regulated in lung cancer. Because the cytoplasmic domain of L-form C-CAM1 is critical for the tumor suppressor function of C-CAM1, we hypothesized that switching of the isoform rather than down- regulation of C-CAM1 gene expression occurs during lung tumorigenesis. To test this hypothesis, we analyzed pairs of tumor tissue and corresponding normal-appearing lung tissue from 51 patients with non-small cell lung cancer (NSCLC) and 43 cell lines to determine expression profiles of L-form C-CAM1 and S-form C-CAM1 using reverse transcription-PCR. We found that L-form C-CAM1 was the predominant form (75%; 38 of 51) in normal-appearing lung tissue, whereas most (84%; 43 of 51) of the primary NSCLC tissue samples expressed predominantly S-form C-CAM1 (P < 0.0001). Similarly, 19 (79%) of the 24 NSCLC cell lines and 17 (85%) of the 20 small cell lung cancer cell lines expressed predominantly S-form C-CAM1. The frequent alteration of the C-CAM1 expression pattern suggests that C-CAM1 has an important role in lung tumorigenesis.