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.

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

“…For example, miR-30c promotes the killing activity of NK cells by up-regulating NKG2D expression [33]. In addition, miR-1245 can directly down-regulate the expression of NKG2D in NK cells, thereby reducing the activity of NK cells [34]. NK cells, which down-regulates the expression of NKG2D in NK cells, thereby inhibiting NK cell activity [35].…”

NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

“…Rs1049174 has been recognized as an eQTL affecting NKG2D expression in several tissues, and recently the underlying molecular mechanism was elucidated. Rs1049174 alleles have differing affinity for micro-RNA mir-1245 that downregulates NKG2D expression (40). In our flow cytometer experiments the studied NKG2D genotypes affected NKG2D expression in both primary cytotoxic cells and in immunoregulatory (CD56bright) NK cells; this finding suggests that NKG2D genotypes may play a role diverse downstream events.…”

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack

“…The cells were then cultured in RPMI 1640 medium containing 10% pooled human serum and 50 U/mL of recombinant IL-2 (PeproTech) and re-stimulated with 0.2 3 10 6 iCD34 1 cells once every 3 days for 2 weeks. Cytotoxicity was evaluated by using a classical 51 Cr release assay, 18 by using a CD107 degranulation assay as described previously, 19 by coculturing the 0.5 3 10 6 cultured CD8 …”