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

Shoib S. Siddiqui, Michael Vaill, Raymond Do, Naazneen Khan, Andrea L. Verhagen, Wu Zhang, Heinz Josef Lenz, Teresa L. Johnson-Pais, Robin J. Leach, Gary Fraser, Charles Wang, Gen Sheng Feng, Nissi Varki, Ajit Varki

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)69-82
Number of pages14
JournalFASEB BioAdvances
Volume3
Issue number2
DOIs
StatePublished - Feb 2021

Keywords

  • SIGLEC12
  • advanced carcinoma
  • dot blot
  • immunohistochemistry
  • pseudogenization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cancer Research
  • Molecular Medicine
  • Physiology

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