RESUMO
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.
Assuntos
Células Matadoras Naturais/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Papillomaviridae/isolamento & purificação , Neoplasias Urogenitais/patologia , Regiões 3' não Traduzidas , Adulto , Idoso , Alelos , Sequência de Bases , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Suscetibilidade a Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genótipo , Células HeLa , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Masculino , MicroRNAs/química , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Polimorfismo de Nucleotídeo Único , Alinhamento de Sequência , Fator de Crescimento Transformador beta1/farmacologia , Neoplasias Urogenitais/virologiaRESUMO
The powerful activating receptor NKG2D is expressed by natural killer (NK) cells and promotes cytotoxic lysis of cancer cells expressing NKG2D ligands (NKG2D-Ls). We report the effective induction of NKG2D-Ls, achieved with the naturally occurring polyphenol resveratrol, in a broad range of leukemia cells. In this study, resveratrol upregulated the NKG2D-Ls MHC class I chain-related proteins MICA and MICB, and UL16-binding proteins ULBP1, ULBP2, and ULBP3 in most of the leukemia cells analyzed. Ligand upregulation induced by resveratrol was impaired by pharmacological and genetic disruption of ataxia-telangiectasia mutated kinase, the main regulator of NKG2D-L expression. Leukemia cells treated with resveratrol were more susceptible to killing by NK cells than untreated cells, and the enhanced cytotoxicity of NK cells was blocked by treatment of NK cells with anti-NKG2D mAbs. Interestingly, resveratrol consistently upregulated the NKG2D receptor expression and enhanced NKG2D-mediated functions in resting NK cells obtained from healthy individuals. Therefore, resveratrol has attractive immunotherapeutic potential.