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1.
Environ Health Perspect ; 124(4): 445-51, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26372664

RESUMEN

BACKGROUND: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development. OBJECTIVES: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas. METHODS: Genetic associations were assessed in a case-control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches. RESULTS: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments. CONCLUSIONS: An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion. CITATION: Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.


Asunto(s)
Carcinoma de Células Escamosas/genética , Interleucina-6/genética , Neoplasias Pulmonares/genética , Neoplasias Inducidas por Radiación/genética , Exposición Profesional/efectos adversos , Radón/toxicidad , Uranio , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/metabolismo , Estudios de Casos y Controles , Estudios de Asociación Genética , Humanos , Interleucina-6/metabolismo , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/metabolismo , Masculino , Mineros , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/metabolismo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo
2.
Carcinogenesis ; 34(5): 1044-50, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23354305

RESUMEN

Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.


Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Minería , Neoplasias Inducidas por Radiación/genética , Enfermedades Profesionales/genética , Sirtuina 1/genética , Uranio/envenenamiento , Alelos , Carcinoma de Células Escamosas/etiología , Estudios de Casos y Controles , Colorado , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Neoplasias Pulmonares/etiología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/etiología , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Polimorfismo de Nucleótido Simple , Radón/envenenamiento
3.
BMC Immunol ; 7: 18, 2006 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-16916450

RESUMEN

BACKGROUND: Deer mice (Peromyscus maniculatus) are the most common mammals in North America and are reservoirs for several zoonotic agents, including Sin Nombre virus (SNV), the principal etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in North America. Unlike human HCPS patients, SNV-infected deer mice show no overt pathological symptoms, despite the presence of virus in the lungs. A neutralizing IgG antibody response occurs, but the virus establishes a persistent infection. Limitations of detailed analysis of deer mouse immune responses to SNV are the lack of reagents and methods for evaluating such responses. RESULTS: We developed real-time PCR-based detection assays for several immune-related transcription factor and cytokine genes from deer mice that permit the profiling of CD4+ helper T cells, including markers of Th1 cells (T-bet, STAT4, IFNgamma, TNF, LT), Th2 cells (GATA-3, STAT6, IL-4, IL-5) and regulatory T cells (Fox-p3, IL-10, TGFbeta1). These assays compare the expression of in vitro antigen-stimulated and unstimulated T cells from individual deer mice. CONCLUSION: We developed molecular methods for profiling immune gene expression in deer mice, including a multiplexed real-time PCR assay for assessing expression of several cytokine and transcription factor genes. These assays should be useful for characterizing the immune responses of experimentally- and naturally-infected deer mice.


Asunto(s)
Perfilación de la Expresión Génica , Peromyscus/genética , Peromyscus/inmunología , Subgrupos de Linfocitos T/metabolismo , Células TH1/metabolismo , Células Th2/metabolismo , Animales , Proliferación Celular , Separación Celular , Células Cultivadas , Citocinas/genética , Subgrupos de Linfocitos T/citología , Células TH1/citología , Células Th2/citología , Factores de Transcripción/genética
4.
BMC Immunol ; 5: 23, 2004 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-15458574

RESUMEN

BACKGROUND: Human infections with Sin Nombre virus (SNV) and related New World hantaviruses often lead to hantavirus cardiopulmonary syndrome (HCPS), a sometimes fatal illness. Lungs of patients who die from HCPS exhibit cytokine-producing mononuclear infiltrates and pronounced pulmonary inflammation. Deer mice (Peromyscus maniculatus) are the principal natural hosts of SNV, in which the virus establishes life-long persistence without conspicuous pathology. Little is known about the mechanisms SNV employs to evade the immune response of deer mice, and experimental examination of this question has been difficult because of a lack of methodologies for examining such responses during infection. One such deficiency is our inability to characterize T cell responses because susceptible syngeneic deer mice are not available. RESULTS: To solve this problem, we have developed an in vitro method of expanding and generating competent antigen presenting cells (APC) from deer mouse bone marrow using commercially-available house mouse (Mus musculus) granulocyte-macrophage colony stimulating factor. These cells are capable of processing and presenting soluble protein to antigen-specific autologous helper T cells in vitro. Inclusion of antigen-specific deer mouse antibody augments T cell stimulation, presumably through Fc receptor-mediated endocytosis. CONCLUSIONS: The use of these APC has allowed us to dramatically expand deer mouse helper T cells in culture and should permit extensive characterization of T cell epitopes. Considering the evolutionary divergence between deer mice and house mice, it is probable that this method will be useful to other investigators using unconventional models of rodent-borne diseases.


Asunto(s)
Peromyscus/genética , Animales , Presentación de Antígeno/fisiología , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/fisiología , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Clonación Molecular/métodos , Epítopos de Linfocito T/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Hemocianinas/inmunología , Antígenos de Histocompatibilidad Clase II/biosíntesis , Humanos , Sueros Inmunes/biosíntesis , Interleucina-2/inmunología , Activación de Linfocitos/fisiología , Ratones , Peromyscus/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Subgrupos de Linfocitos T/fisiología , Linfocitos T Colaboradores-Inductores/fisiología
5.
J Pharmacol Exp Ther ; 311(2): 758-69, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15231866

RESUMEN

We used primary peripheral blood T cells, a population that exists in G(0) and can be stimulated to enter the cell cycle synchronously, to define more precisely the effects of nicotine on pathways that control cell cycle entry and progression. Our data show that nicotine decreased the ability of T cells to transit through the G(0)/G(1) boundary (acquire competence) and respond to progression signals. These effects were due to nuclear factor of activated T cells c2 (NFATc2)-dependent repression of cyclin-dependent kinase 4 (CDK4) expression. Growth arrest at the G(0)/G(1) boundary was further enforced by inhibition of cyclin D2 expression and by increased expression and stabilization of p27Kip1. Intriguingly, T cells from habitual users of tobacco products and from NFATc2-deficient mice constitutively expressed CDK4 and were resistant to the antiproliferative effects of nicotine. These results indicate that nicotine impairs T cell cycle entry through NFATc2-dependent mechanisms and suggest that, in the face of chronic nicotine exposure, selection may favor cells that can evade these effects. We postulate that cross talk between nicotinic acetylcholine receptors and growth factor receptor-activated pathways offers a novel mechanism by which nicotine may directly impinge on cell cycle progression. This offers insight into possible reasons that underlie the unique effects of nicotine on distinct cell types and identifies new targets that may be useful control tobacco-related diseases.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Nicotina/farmacología , Proteínas Nucleares/metabolismo , Linfocitos T/efectos de los fármacos , Factores de Transcripción/metabolismo , Animales , Calcio/metabolismo , Células Cultivadas , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Citocinas/farmacología , Proteínas de Unión al ADN/fisiología , Humanos , Ratones , Factores de Transcripción NFATC , Proteínas Nucleares/fisiología , Fenotipo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Linfocitos T/citología , Nicotiana/química , Factores de Transcripción/fisiología
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