Human‐specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression

Abstract

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.

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing

“…Higher SCARF1 expression in hepatocellular carcinoma tumor tissues was highly prognostic of better OS, DFS and PFS [67]. High frequency of SIGLEC12 expression in advanced colorectal cancer cohort and correlation with OS [68]. TGM2 has been shown to enhance the migration and invasion of lung cancer cells [69].…”

“…The pathway with the largest number of associated genes is the mitogen-activated protein kinases (MAPKs) signaling pathway. Eight genes could regulate it, and they are AKAP2 [72], ALOX5 [63], GCGR [73], NLRP12 [74], NTSR1 [75], PF4 [76], SIGLEC12 [68] and TGM2 [77]. Wnt/β-catenin signaling pathway could be regulated by AKAP2 [55], ALOX5 [78] and TGM2 [79].…”

Siglecs as Therapeutic Targets in Cancer

“…Nonetheless, Siglec-XII is able to recruit SHP2-related oncogenic pathways. An elevated Siglec-XII level is also associated with advanced colorectal cancer and poor OS in patients [139].…”

Analysis of SIGLEC12 expression, immunomodulation and prognostic value in renal cancer using multiomic databases

“…Through binding with preferred sialogycans, they initiate intracellular signalling to recruit protein tyrosine phosphatases Src-homology 2 domain (SH2)-containing phosphatase 1 (SHP-1) and SHP-2, thereby participating in the numerous signalling cascades that influence cellular immune inhibition [ 9 ]. Report indicate that human Siglec-XII a family of CD33rSiglecs, is expressed in approximately ∼30–40 % of the sub-Saharan African population, while a high incidence of about ∼75–90 % expression is observed in the Native American populace [ 15 ].…”

“…However, Siglec-XII has been linked as a non-functional protein with atypism in different ways [ 15 ]. Firstly, it is unable to recognize Sias due to a human-universal mutation of critical arginine residues present in both domains of the V-set.…”