Compared with our closest living evolutionary cousins, humans appear unusually prone to develop
carcinomas (
cancers arising from epithelia). 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. Despite the loss of canonical
sialic acid binding,
Siglec-XII still recruits Shp2 and accelerates
tumor growth in a mouse model. We hypothesized that dysfunctional
Siglec-XII facilitates human
carcinoma progression, correlating with known tumorigenic signatures of Shp2-dependent
cancers. Immunohistochemistry was used to detect
Siglec-XII expression on tissue microarrays. PC-3
prostate cancer cells were transfected with
Siglec-XII and transcription of genes enriched with
Siglec-XII was determined. Genomic SIGLEC12 status was determined for four different
cancer cohorts. Finally, a dot blot analysis of human urinary epithelial cells was established to determine the
Siglec-XII expressors versus non-expressors. Forced expression in a SIGLEC12 null
carcinoma cell line enriched transcription of genes associated with
cancer progression. 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. Thus, advanced
carcinomas are much more likely to occur in individuals whose genomes have an intact SIGLEC12 gene, likely because the encoded
Siglec-XII
protein recruits Shp2-related oncogenic pathways. The finding has prognostic, diagnostic, and therapeutic implications.