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The multifunctional Ig-like carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is neo-expressed in the majority of malignant melanoma lesions. CEACAM1 acts as a driver of tumor cell invasion, and its expression correlates with poor patient prognosis. Despite its importance in melanoma progression, how CEACAM1 expression is regulated is largely unknown. Here, we show that CEACAM1 expression in melanoma cell lines and melanoma tissue strongly correlates with that of the microphthalmia-associated transcription factor (MITF), a key regulator of melanoma proliferation and invasiveness. MITF is revealed as a direct and positive regulator for CEACAM1 expression via binding to an M-box motif located in the CEACAM1 promoter. Taken together, our study provides novel insights into the regulation of CEACAM1 expression and suggests an MITF-CEACAM1 axis as a potential determinant of melanoma progression.

CEACAM1 is a widely expressed multifunctional cell–cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study, we examine the functional and clinical contributions of the four splice isoforms of CEACAM1. Specifically, we present in vitro and in vivo evidence that they affect melanoma progression and immune surveillance in a negative or positive manner that is isoform specific in action. In contrast with isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which was mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEACAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biologic functions of CEACAM1 in melanoma pathogenesis. Cancer Res; 75(9); 1897–907. ©2015 AACR.