SIGLEC12 gene could be the cause behind many cancers

Researchers have discovered that SIGLEC12 contains several features unique to humans

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Epithelial carcinoma

HOBOKEN, N.J.—New research, recently published in FASEB BioAdvances, has revealed a human-specific connection between advanced carcinomas and a gene called SIGLEC12.

Humans are more prone to developing carcinomas when we’re compared to our closest evolutionary cousins, the great apes. These cancers begin in epithelial cells of the skin, or the tissue that covers the surface of internal organs and glands — including prostate, breast, lung and colorectal cancers.

Additional studies related to this gene, which has several uniquely human features — and the protein it encodes, called Siglec-XII — could potentially lead to advances in cancer prognostics, diagnostics and therapeutics.

“The SIGLEC12 gene, which encodes the Siglec-XII protein expressed on epithelial cells, has several uniquely human features: a fixed homozygous missense mutation inactivating its natural ligand recognition property; a polymorphic frameshift mutation eliminating full-length protein expression in ~60%–70% of worldwide human populations; and genomic features suggesting a negative selective sweep favoring the pseudogene state,” the article notes.

“Siglecs are typically expressed in immune cells, and it was surprising to find Siglec-XII on epithelial surfaces,” said Nissi Varki, M.D., professor of Pathology at the University of California San Diego School of Medicine, and co-author of the study. “While a mutant form of Siglec-XII is expressed only in about 30% of normal humans, it was found to be present in a high proportion of advanced carcinomas. This could help explain why humans are more prone to aggressive carcinomas, which are rare in chimpanzees.”

“Forced expression in a SIGLEC12 null carcinoma cell line enriched transcription of genes associated with cancer progression,” the article explains. “While Siglec-XII was detected as expected in ~30%–40% of normal epithelia, ~80% of advanced carcinomas showed strong expression. Notably, >80% of late-stage colorectal cancers had a functional SIGLEC12 allele, correlating with overall increased mortality.”

“This first study of a very unusual phenomenon raises even more questions than answers. We do not know if there is still any definite ligand for Siglec-XII,” points out the article. “It does not bind with Sias, but we cannot rule out its interaction with another unknown ligand(s).”

“Conversely, we can also consider the hypothesis that this is a constitutively active receptor, which does not need any ligand for its activation. This aspect of Siglec biology is not extensively studied,” the article continues. “Second, we did not study the signaling pathways mediated by SiglecXII-Shp2 axis. Third, we have not yet done the gene expression analysis in PC-3 cells with Shp2 inhibitors.”

More work is needed to fully understand SIGLEC12, and the study states that a knockdown in a Siglec-XII expressing cell line will be informative, especially for future studies that expand on these findings.

“Regardless, we have previously noted that triggering of endocytosis by antibodies against this receptor can deliver toxins into the cell. In analogy to the targeting of Siglec-3/CD33 human leukemias, a similar approach could be taken for treatment of late-stage carcinomas. Our simple urine screen should be of value in these and other clinical studies,” the article concludes.

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