CEACAM1 Promotes Melanoma Cell

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 directeffectsofCEACAM1onmelanomacellbiology.Byemployingtissuemicroarraysandlow-passageprimarycultures of metastatic melanoma, we show that CEACAM1 expression gradually increases from nevi to metastatic specimens, withastrongdominanceoftheCEACAM1-Longtailsplicevariant.UsingexperimentalsystemsofCEACAM1knockdown 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 onthe role of CEACAM1 in melanoma, forming the basis for development of novel therapeutic and diagnostic technologies.