Melanoma is a deadly malignancy responsible for 75% of death cases due to skin cancer. CEACAM1 is a membranal glycoprotein, which is subjected to alternative splicing giving rise to a long cytoplasmic tail variant that transduces intracellular signals, and to a short tail variant. The expression of CEACAM1 on primary melanoma strongly predicts an aggressive disease. We show in progression tissue microarray that CEACAM1 is gradually upregulated during melanoma development and progression, and that there is 4-fold dominance of the long variant on average.
Knockdown of CEACAM1 significantly reduce the net proliferation of CEACAM1(+) 526mel melanoma cells. Conversely, over-expression of the CEACAM1-Long but not the CEACAM1-Short significantly enhances the net proliferation of CEACAM1(-) 003mel melanoma cells. Furthermore, these cells demonstrate higher tumorigenicity when injected SC into SCID-NOD mice. The tumorigenic effect of CEACAM1-Long is mediated by Y488, S503 and Y515 in the cytoplasmic tail, and is carried out in a SOX2-dependent manner.
Sequencing of 135 germ-line DNA samples derived from melanoma patients and 135 samples from matched healthy donors reveals two SNP variants in the promoter region of CEACAM1, rs8103285 (G\A) and rs8102519 (C/T). The melanoma patients deviate from the Hardy Weinberg Equilibrium as compared to the healthy group, and remarkably, homozygocity increases the chances to develop melanoma by 35%. Accordingly, reporter constructs mimicking these SNPs show significantly enhances promoter function activity.
In conclusion, we reveal a new mechanism of melanoma progression as well as a new genetic factor that may affect CEACAM1 expression in melanoma.
