CEACAM1 Promotes Melanoma Cell Growth through Sox-2

Abstract

The prognostic value of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in melanoma was demonstrated more than a decade ago as superior to Breslow score. We have previously shown that intercellular homophilic CEACAM1 interactions protect melanoma cells from lymphocyte-mediated elimination. Here, we study the direct effects of CEACAM1 on melanoma cell biology. By employing tissue microarrays and low-passage primary cultures of metastatic melanoma, we show that CEACAM1 expression gradually increases from nevi to metastatic specimens, with a strong dominance of the CEACAM1-Long tail splice variant. Using experimental systems of CEACAM1 knockdown and overexpression of selective variants or truncation mutants, we prove that only the full-length long tail variant enhances melanoma cell proliferation in vitro and in vivo. This effect is not reversed with a CEACAM1-blocking antibody, suggesting that it is not mediated by intercellular homophilic interactions. Downstream, CEACAM1-Long increases the expression of Sox-2, which we show to be responsible for the CEACAM1-mediated enhanced proliferation. Furthermore, analysis of the CEACAM1 promoter reveals two single-nucleotide polymorphisms (SNPs) that significantly enhance the promoter's activity compared with the consensus nucleotides. Importantly, case-control genetic SNP analysis of 134 patients with melanoma and matched healthy donors show that patients with melanoma do not exhibit the Hardy-Weinberg balance and that homozygous SNP genotype enhances the hazard ratio to develop melanoma by 35%. These observations shed new mechanistic light on the role of CEACAM1 in melanoma, forming the basis for development of novel therapeutic and diagnostic technologies.

Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells

“…C). This adhesion molecule was already found to show gradually increasing expression from melanocytic nevi to metastatic specimens and to be a prognostic marker for melanoma . This proves that partial reprogramming of melanoma cells is a suitable system to find novel biomarkers for early melanoma progression and patient stratification.…”

A longitudinal study of CEACAM1 expression in melanoma disease progression

“…several studies have shown that normal melanocytes do not express CEACAM1 while most malignant melanoma lesions do express CEACAM1 (10,20). We previously demonstrated that up to 89% of metastatic melanoma lesions are positive for CEACAM1 (6,10) and that its expression increases concomitantly with tumor development and progression (10).…”

“…CEACAM1 is a transmembranal glycoprotein belonging to the Ig superfamily, composed of several extracellular Ig-like domains (7). CEACAM1 has been shown to be involved in the development of cancerous transformation, particularly in melanoma, yet also in non-small cell lung cancer and gastric carcinoma (8)(9)(10). Importantly, a strong correlation between CEACAM1 expression and the development of metastatic disease with poor overall survival was demonstrated in melanoma (11) and in lung cancer (12,13).…”

Cold Atmospheric Plasma Restores Paclitaxel Sensitivity to Paclitaxel-Resistant Breast Cancer Cells by Reversing Expression of Resistance-Related Genes

“…CEACAM1 is a glycoprotein belonging to the carcinoembryonic antigen (CEA) family that is expressed in a wide variety of cells [32]. The prognostic value of CEACAM1 in cancer is controversial: CEACAM1 expression correlates with good prognosis in mammary carcinomas, whereas in melanomas, upregulation of CEACAM1 is accompanied by poor overall survival [33,34]. It is notable that CEACAM1 was upregulated in the MCF-7/TxR cells and downregulated by CAP.…”