A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers

• Published in: Scientific reports 2016-12, Vol.6 (1), p.39231-39231, Article 39231
• Main Authors: Espinoza, J. Luis, Nguyen, Viet H., Ichimura, Hiroshi, Pham, Trang T. T., Nguyen, Cuong H., Pham, Thuc V., Elbadry, Mahmoud I., Yoshioka, Katsuji, Tanaka, Junji, Trung, Ly Q., Takami, Akiyoshi, Nakao, Shinji
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/21; 13/31; 3' Untranslated Regions; 38/109; 631/250/2502/248; 631/67/2324; 692/4028/67/580/1884/2323; 82; 96/106; Adult; Aged; Alleles; Anogenital; Base Sequence; Cancer; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Cervical cancer; Cervix; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Disease Susceptibility; Female; Gene Expression Regulation, Neoplastic; Gene Frequency; Gene polymorphism; Genital cancers; Genotype; Genotype & phenotype; HeLa Cells; Human papillomavirus; Humanities and Social Sciences; Humans; Immunosurveillance; Interferon-gamma - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Male; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; multidisciplinary; NK Cell Lectin-Like Receptor Subfamily K - antagonists & inhibitors; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NKG2 antigen; Papillomaviridae - isolation & purification; Polymorphism, Single Nucleotide; Science; Sequence Alignment; Transforming Growth Factor beta1 - pharmacology; Urogenital Neoplasms - pathology; Urogenital Neoplasms - virology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39231

Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and is etiologically linked to several cancers, including cervical and genital cancers. NKG2D, an activating receptor expressed by NK cells, plays an important role in cancer immune-surveillance. We analyzed the impact of a NKG2D gene variant, rs1049174, on the incidence of HPV-related cancers in Vietnamese patients and utilized various molecular approaches to elucidate the mechanisms of NKG2D receptor regulation by rs1049174. In a group of 123 patients with HPV+ anogenital cancers, the low cytotoxicity allele LNK was significantly associated with increased cancer susceptibility (p = 0.016). Similar results were also observed in a group of 153 women with cervical cancer (p = 0.05). In functional studies, NK cells from individuals with LNK genotype showed a lower NKG2D expression and displayed less efficient NKG2D-mediated functions than NK cells with HNK genotype. Notably, the rs1049174 variant occurs within a targeting site for miR-1245, a negative regulator of NKG2D expression. Compared with the higher cytotoxicity allele HNK, the LNK allele was more efficiently targeted by miR-1245 and thus determined lower NKG2D expression in NK cells with the LNK genotype. The NKG2D variants may influence cancer immunosurveillance and thus determine susceptibility to various malignancies, including HPV-induced cancers.