RESUMEN
Siglecs belong to a family of immune regulatory receptors predominantly found on hematopoietic cells. They interact with Sia, resulting in the activation or inhibition of the immune response. Previous reports have suggested that the SIGLEC12 gene, which encodes the Siglec-XII protein, is expressed in the epithelial tissues and upregulated in carcinomas. However, studies deciphering the role of Siglec-XII in renal cancer (RC) are still unavailable, and here we provide insights on this question. We conducted expression analysis using the Human Protein Atlas and UALCAN databases. The impact of SIGLEC12 on RC prognosis was determined using the KM plotter, and an assessment of immune infiltration with SIGLEC12 was performed using the TIMER database. GSEA was conducted to identify the pathways affected by SIGLEC12. Finally, using GeneMania, we identified Siglec-XII interacting proteins. Our findings indicated that macrophages express SIGLEC12 in the kidney. Furthermore, we hypothesize that Siglec-XII expression might be involved in the increase of primary RC, but this effect may not be dependent on the age of the patient. In the tumour microenvironment, oncogenic pathways appeared to be upregulated by SIGLEC12. Similarly, our analysis suggested that SIGLEC12-related kidney renal papillary cell carcinomas may be more suitable for targeted immunotherapy, such as CTLA-4 and PD-1/PD-L1 inhibitors. These preliminary results suggested that high expression of SIGLEC12 is associated with poor prognosis for RC. Future studies to assess its clinical utility are necessitated.
RESUMEN
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.