SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

Abstract

The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.Sialic acids (Sias) 5 are nine-carbon backbone sugar molecules typically found at terminal positions of glycan chains in Deuterostomes (vertebrates and some "higher" invertebrates), making them potentially important in recognition events (1-3). One class of intrinsic Sia recognition proteins in vertebrates are Siglecs (sialic acid-binding immunoglobulin-like lectins). Siglecs are single-pass transmembrane proteins, with a Siabinding site in the extracellular N-terminal Ig-like V-set domain (4 -9). Such V-set domains are followed by one or more C2-set Ig-like domains. Siglecs can signal through one or more tyrosine-based signaling motif(s) in the cytoplasmic tail (5,8,9).CD33-related Siglecs (CD33rSiglecs) are encoded by a subset of SIGLEC genes clustered on chromosome 19 in humans and chimpanzees. They are homologous in sequence and typically expressed on immune cells (10). Analyses of genomic SIGLEC sequences across humans, chimpanzees, baboons, rats, and mice showed that CD33rSiglecs are evolving rapidly (11). This is particularly pronounced in the Sia-recognizing V-set domain, suggesting that this domain is under the greatest selection pressure (11)(12)(13)(14).This study focuses on Siglec-12 (formerly Siglec-L1). We have shown previously that human Siglec-12 has an Arg 3 Cys (R122C) substitution m...

Siglec-mediated regulation of immune cell function in disease

“… 1 Two additional Siglec genes/proteins are found in chimpanzees that are either only expressed in some humans in a form that does not bind sialic acids (Siglec-12), or have been deleted from the human genome (Siglec-13) 147, 148 . 2 Specificities are summarized from the cited references or from glycan array data at the http://www.functionalglycomics.org. ND is not determined.…”

“… 1 Two additional Siglec genes/proteins are found in chimpanzees that are either only expressed in some humans in a form that does not bind sialic acids (Siglec-12), or have been deleted from the human genome (Siglec-13) 147, 148 . …”

Prostate Cancer and Immunoproteome: Awakening and Reprogramming the Guardian Angels

“…To further investigate these findings, prostate cancer cells were stably transfected with Siglec-XII that consequently enhanced proliferation potential of the cells in nude mice. However, interestingly, mAb directed against the protein were internalized by Siglec-XII-expressing cancer cells, allowing targeting of a toxin to prostate cancer cells (Mitra et al 2011). In the context of targeted therapy, the possibility of developing a drug delivery nanocarrier capable to specifically reach cancer cells cannot be overlooked.…”

Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes

“…Most siglecs are differentially expressed on hematopoietic and immune cells. So far, the exceptions are, Siglec-4 (myelin-associated glycoprotein, MAG) on glial cells14, Siglec-5 and 14 on human amniotic epithelium15, Siglec-6 on the human placental trophoblast16, Siglec-11 on ovarian fibroblasts17 and Siglec-12 on certain hominid epithelial cells1819.…”