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

Autor: Siddiqui SS; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA.; Present address: Department of Biotechnology American University of Ras Al Khaimah (AURAK American University of Ras Al Khaimah Road Al Burairat Area Ras Al Khaimah UAE., Vaill M; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Do R; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Khan N; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Verhagen AL; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Zhang W; University of Southern California Norris Comprehensive Cancer Center Los Angeles CA USA., Lenz HJ; University of Southern California Norris Comprehensive Cancer Center Los Angeles CA USA., Johnson-Pais TL; Department of Urology University of TX Health Science Center San Antonio TX USA., Leach RJ; Department of Urology University of TX Health Science Center San Antonio TX USA.; Departments of Cell Systems and Anatomy University of TX Health Science Center San Antonio TX USA., Fraser G; School of Public Health Loma Linda University Loma Linda CA USA., Wang C; School of Public Health Loma Linda University Loma Linda CA USA., Feng GS; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Varki N; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA., Varki A; Departments of Medicine, Cellular and Molecular Medicine, and Pathology, Glycobiology Research and Training Cente and Center for Academic Research and Training in Anthropogeny University of California San Diego CA USA.
Jazyk: angličtina
Zdroj: FASEB bioAdvances [FASEB Bioadv] 2020 Dec 08; Vol. 3 (2), pp. 69-82. Date of Electronic Publication: 2020 Dec 08 (Print Publication: 2021).
DOI: 10.1096/fba.2020-00092
Abstrakt: 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.
Competing Interests: The authors declare no competing interest with the content of this manuscript.
(© 2020 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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