title: A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers.
abstract: 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.
authors.affiliation: Cellular transplantation Biology, Kanazawa University, Kanazawa, Japan.
authors.forename: J Luis
authors.initials: JL
authors.lastname: Espinoza
authors.affiliation: Cellular transplantation Biology, Kanazawa University, Kanazawa, Japan.
authors.forename: Viet H
authors.initials: VH
authors.lastname: Nguyen
authors.affiliation: Department of viral infection and International Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichimura
authors.affiliation: Department of viral infection and International Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Trang T T
authors.initials: TT
authors.lastname: Pham
authors.affiliation: Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam.
authors.forename: Cuong H
authors.initials: CH
authors.lastname: Nguyen
authors.affiliation: Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam.
authors.forename: Thuc V
authors.initials: TV
authors.lastname: Pham
authors.affiliation: Cellular transplantation Biology, Kanazawa University, Kanazawa, Japan.
authors.forename: Mahmoud I
authors.initials: MI
authors.lastname: Elbadry
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Division of Virology, Department of Laboratory Science, School of Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Soc Trang Provincial Hospital, Soc Trang, Vietnam.
authors.forename: Ly Q
authors.initials: LQ
authors.lastname: Trung
authors.affiliation: Department of Internal Medicine, Division of Hematology, Aichi Medical University, Nagoya, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Takami
authors.affiliation: Cellular transplantation Biology, Kanazawa University, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004198:Disease Susceptibility; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D027383:Papillomaviridae / Q000302:isolation & purification*; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014565:Urogenital Neoplasms / Q000473:pathology* / Q000821:virology
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma