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Insulinoma/genética , Mutación , Neoplasias Pancreáticas/genética , Factor de Transcripción YY1/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular Tumoral , Análisis Mutacional de ADN/métodos , Insulinoma/patología , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/patología , Neoplasias Pancreáticas/patología , Ratas , Rayos XRESUMEN
Furocoumarins are a class of compounds produced by several plant species, including some popularly consumed by humans. Furocoumarins are known to be well absorbed from food sources, and can be rapidly distributed into several tissues including the skin. In human skin, when exposed to UV radiation, furocoumarins may become photoactivated and form interstrand crosslinks with DNA, thereby disrupting DNA transcription. Because of this property, furocoumarins have been combined as topical or oral agents with UV irradiation as a phototherapy to treat multiple skin conditions, yet these treatments have been shown to increase risk of both melanoma and non-melanoma skin cancer. Whether or not dietary furocoumarin exposure may confer the same risk is not yet known. This review summarizes the current evidence regarding the activities of ingested furocoumarins, with particular focus on how dietary furocoumarins are absorbed, metabolized, and distributed throughout the body, and their interactions with various cellular components that may underlie a potential relationship with skin cancer.
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Furocumarinas/farmacocinética , Neoplasias Inducidas por Radiación/etiología , Neoplasias Cutáneas/etiología , Animales , Carcinógenos/toxicidad , Aductos de ADN/química , Replicación del ADN/efectos de los fármacos , Exposición Dietética , Furocumarinas/efectos adversos , Humanos , Neoplasias Inducidas por Radiación/genética , Fotoquimioterapia , Plantas Comestibles/química , Neoplasias Cutáneas/genética , Distribución Tisular , Rayos UltravioletaRESUMEN
PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
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Carcinógenos Ambientales/toxicidad , Neoplasias Pulmonares/genética , Neoplasias Inducidas por Radiación/genética , Proteínas del Tejido Nervioso/genética , Enfermedades Profesionales/genética , Radón/toxicidad , Receptores Nicotínicos/genética , Estudios de Casos y Controles , Daño del ADN/efectos de la radiación , Femenino , Marcadores Genéticos/efectos de la radiación , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Minería , Exposición Profesional/efectos adversos , Factores de Riesgo , Ubiquitinación/efectos de la radiación , UranioRESUMEN
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.
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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/metabolismoRESUMEN
BACKGROUND: Multifocal papillary thyroid carcinoma (MPTC) has been reported in literature in 18-87 % of cases. This paper aims to review controversies in the molecular pathogenesis, prognosis, and management of MPTC. METHODS: A review of English-language literature focusing on MPTC was carried out, and analyzed in an evidence-based perspective. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to surgery of thyroid carcinoma. RESULTS: Literature reports no prospective randomized studies; thus, a relatively low level of evidence may be achieved. CONCLUSIONS: MPTC could be the result of either true multicentricity or intrathyroidal metastasis from a single malignant focus. Radiation and familial nonmedullary thyroid carcinoma are conditions at risk of MPTC development. The prognostic importance of multifocal tumor growth in PTC remains controversial. Prognosis might be impaired in clinical MPTC but less or none in MPTC <1 cm. MPTC can be diagnosed preoperatively by FNAB and US, with low sensitivity for MPTC <1 cm. Total or near-total thyroidectomy is indicated to reduce the risk of local recurrence. Prophylactic central node dissection should be considered in patients with total tumor diameter >1 cm, or in cases with high number of cancer foci. Completion thyroidectomy might be necessary when MPTC is diagnosed after less than near-total thyroidectomy. Radioactive iodine ablation should be considered in selected patients with MPTC at increased risk of recurrence or metastatic spread.
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Adenocarcinoma Papilar/cirugía , Neoplasias Primarias Múltiples/cirugía , Neoplasias de la Tiroides/cirugía , Adenocarcinoma Papilar/diagnóstico , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Accidente Nuclear de Chernóbil , Terapia Combinada , Análisis Mutacional de ADN , Progresión de la Enfermedad , Europa (Continente) , Disección del Cuello , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/patología , Neoplasias Inducidas por Radiación/cirugía , Pronóstico , Radioterapia Adyuvante , Factores de Riesgo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , TiroidectomíaRESUMEN
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.
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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/envenenamientoRESUMEN
Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD(+) cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD(+) cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB-induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD(+) cells in xeroderma pigmentosum complementation group A (XPA)-proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms.
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Reparación del ADN/efectos de los fármacos , Extracto de Semillas de Uva/uso terapéutico , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/prevención & control , Proantocianidinas/uso terapéutico , Rayos Ultravioleta , Proteína de la Xerodermia Pigmentosa del Grupo A/fisiología , Animales , Western Blotting , Daño del ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Dieta , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Técnicas para Inmunoenzimas , Interleucina-12/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Dímeros de Pirimidina/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vitis/químicaRESUMEN
Depleted uranium (DU) is an alpha particle emitter and radioactive heavy metal used in military applications. Due to internalization of DU during military operations and the ensuing chronic internal exposure to DU, there are concerns regarding its potential health effects. Preconceptional paternal irradiation has been implicated as a causal factor in childhood cancer and it has been suggested that this paternal exposure to radiation may play a role in the occurrence of leukemia and other cancers to offspring. Similarly, in vivo heavy metal studies have demonstrated that carcinogenic effects can occur in unexposed offspring. Using a transgenic mouse system employing a lambda shuttle vector allowing mutations (in the lacI gene) to be analyzed in vitro, we have investigated the possibility that chronic preconceptional paternal DU exposure can lead to transgenerational transmission of genomic instability. The mutation frequencies in vector recovered from the bone marrow cells of the F1 offspring of male parents exposed to low, medium, and high doses of internalized DU for 7 mo were evaluated and compared to control, tantalum, nickel, and gamma radiation F1 samples. Results demonstrate that as paternal DU-dose increased there was a trend towards higher mutation frequency in vector recovered from the DNA obtained from bone marrow of F1 progeny; medium and high dose DU exposure to P1 fathers resulted in a significant increase in mutation frequency in F1 offspring (3.57 +or - 0.37 and 4.81 + or - 0.43 x 10; p < 0.001) in comparison to control (2.28 + or - 0.31 x 10). The mutation frequencies from F1 offspring of low dose DU, Ta- or Ni-implanted fathers (2. 71 + or - 0.35, 2.38 + or - 0.35, and 2.93 + or - 0.39 x 10, respectively) were not significantly different than control levels (2.28 + or - 0.31 x 10). Offspring from Co (4 Gy) irradiated fathers did demonstrate an increased lacI mutation frequency (4.69 + or - 0.48 x 10) as had been shown previously. To evaluate the role of radiation involved in the observed DU effects, males were exposed to equal concentrations (50 mg U L) of either enriched uranium or DU in their drinking water for 2 mo prior to breeding. A comparison of these offspring indicated that there was a specific-activity dependent increase in offspring bone marrow mutation frequency. Taken together these uranyl nitrate data support earlier results in other model systems showing that radiation can play a role in DU-induced biological effects in vitro. However, since the lacI mutation model measures point mutations and cannot measure large deletions that are characteristic of radiation damage, the role of DU chemical effects in the observed offspring mutation frequency increase may also be significant. Regardless of the question of DU-radiation vs. DU-chemical effects, the data indicate that there exists a route for transgenerational transmission of factor(s) leading to genomic instability in F1 progeny from DU-exposed fathers.
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Inestabilidad Genómica/genética , Inestabilidad Genómica/efectos de la radiación , Neoplasias Inducidas por Radiación/inducido químicamente , Exposición Paterna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Uranio/toxicidad , Partículas alfa , Animales , Médula Ósea/metabolismo , Médula Ósea/efectos de la radiación , Daño del ADN/genética , Relación Dosis-Respuesta en la Radiación , Femenino , Represoras Lac/genética , Leucemia/inducido químicamente , Leucemia/genética , Leucemia/metabolismo , Masculino , Ratones , Ratones Transgénicos , Mutación , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Uranio/metabolismoRESUMEN
The human ortholog of Monodelphis translocon-associated protein delta subunit gene (TRAPD) was identified as a differentially expressed transcript using the differential display technique, and the two phenotypically distinct opossum melanoma cell lines TD6b and TD15L2 as the tissue resource. The full-length cDNA of TRAPD that encodes a 144 amino acid protein was characterized. In addition, a relative quantitative reverse transcription-polymerase chain reaction approach was used to analyse the expression patterns of TRAPD during different stages of tumour progression. TRAPD was upregulated in tumours of advanced stages. The results of this study implicate TRAPD as a candidate gene with potential functions that might be associated with ultraviolet-induced melanomagenesis and metastasis.
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Proteínas de Unión al Calcio/genética , Melanoma/genética , Glicoproteínas de Membrana/genética , Neoplasias Inducidas por Radiación/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Péptidos/genética , Rayos Ultravioleta , Animales , Secuencia de Bases , Proteínas de Unión al Calcio/química , Línea Celular Tumoral , Clonación Molecular , ADN Complementario/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glicoproteínas de Membrana/química , Datos de Secuencia Molecular , Estadificación de Neoplasias , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/química , Receptores de Péptidos/química , Análisis de Secuencia de ADN , Análisis de Secuencia de ProteínaRESUMEN
Psoriasis patients exposed to high cumulative doses of psoralen + ultraviolet A frequently exhibit so-called "psoralen + ultraviolet A keratoses" (i.e., hyperkeratotic lesions with varying degrees of histologic atypia). The exact causes and molecular mechanisms of psoralen + ultraviolet A keratoses however, are not clear. We therefore performed DNA mutational analysis of the tumor suppressor gene p53 (exons in psoralen + ultraviolet A keratoses from 10 long-term psoralen + ultraviolet A-treated psoriasis patients. We detected 39 p53 mutations in 16 of 28 psoralen + ultraviolet A keratoses (57%) and 18 Ha-ras mutations in 11 of 25 psoralen + ultraviolet A keratoses (44%). Of the 39 p53 mutations and 18 Ha-ras mutations, 22 (56%) and 13 (72%), respectively, were of the ultraviolet fingerprint type (C-->T or CC-->TT transitions at dipyrimidine sites); 13 (33%) and two (11%), respectively, occurred at potential psoralen-binding sites (5'-TpA, 5'-TpG, or 5'-TpT DNA sequences) and were potentially psoralen + ultraviolet A induced; two (5%) and three (17%), respectively, were of ambiguous origin (ultraviolet and/or psoralen + ultraviolet A); and two (5%) and none (0%), respectively, were of the "other" type, respectively. We conclude that (1) the frequent mutation of p53 and Ha-ras may play a key part in the formation of at least some psoralen + ultraviolet A keratoses; (2) environmental and/or therapeutic ultraviolet exposure may be a major cause of psoralen + ultraviolet A keratosis as most Ha-ras and p53 mutations are induced by ultraviolet light; and (3) psoralen + ultraviolet A itself plays a smaller, though direct, role in causing these mutations.
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Ficusina/efectos adversos , Genes p53/efectos de la radiación , Genes ras/efectos de la radiación , Terapia PUVA/efectos adversos , Psoriasis/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Adulto , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/genética , Femenino , Genes p53/genética , Genes ras/genética , Humanos , Queratosis/tratamiento farmacológico , Queratosis/epidemiología , Queratosis/patología , Masculino , Persona de Mediana Edad , Mutación Missense , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/genética , Psoriasis/epidemiología , Psoriasis/patología , Factores de Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Rayos UltravioletaRESUMEN
Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) protect against photocarcinogenesis in animals, but prospective human studies are scarce. The mechanism(s) underlying the photoprotection are uncertain, although omega-3 PUFAs may influence oxidative stress. We examined the effect of supplementation on a range of indicators of ultraviolet radiation (UVR)-induced DNA damage in humans, and assessed effect on basal and post-UVR oxidative status. In a double-blind randomized study, 42 healthy subjects took 4 g daily of purified omega-3 PUFA, eicosapentaenoic acid (EPA), or monounsaturated, oleic acid (OA), for 3 months. EPA was bioavailable; the skin content at 3 months showing an 8-fold rise from baseline, P < 0.01. No consistent pattern of alteration in basal and UVR-exposed skin content of the antioxidants glutathione, vitamins E and C or lipid peroxidation, was seen on supplementation. Sunburn sensitivity was reduced on EPA, the UVR-induced erythemal threshold rising from a mean of 36 (SD 10) mJ/cm(2) at baseline to 49 (16) mJ/cm(2) after supplementation, P < 0.01. Moreover, UVR-induced skin p53 expression, assessed immunohistochemically at 24 h post-UVR exposure, fell from a mean of 16 (SD 5) positive cells/100 epidermal cells at baseline to 8 (4) after EPA supplementation, P < 0.01. Peripheral blood lymphocytes (PBL) sampled on 3 successive days both pre- and post-supplementation, showed no change with respect to basal DNA single-strand breaks or oxidative base modification (8-oxo-dG). However, when susceptibility of PBL to ex vivo UVR was examined using the comet assay, this revealed a reduction in tail moment from 84.4 (SD 3.4) at baseline to 69.4 (3.1) after EPA, P = 0.03. No significant changes were seen in any of the above parameters following OA supplementation. Reduction in this range of early markers, i.e. sunburn, UVR-induced p53 in skin and strand breaks in PBL, indicate protection by dietary EPA against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans.
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Ácido Eicosapentaenoico/farmacología , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Cutáneas/prevención & control , Piel/efectos de la radiación , Adulto , Anciano , Ácido Ascórbico/metabolismo , Disponibilidad Biológica , ADN/efectos de la radiación , Daño del ADN , Reparación del ADN , Suplementos Dietéticos , Método Doble Ciego , Ácido Eicosapentaenoico/farmacocinética , Femenino , Marcadores Genéticos , Glutatión/metabolismo , Humanos , Peroxidación de Lípido , Linfocitos/efectos de la radiación , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/genética , Ácido Oléico/farmacocinética , Ácido Oléico/farmacología , Piel/metabolismo , Neoplasias Cutáneas/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Rayos Ultravioleta , Vitamina E/metabolismoRESUMEN
Recent genetic studies of tumorigenesis have strongly suggested an existence of tumor suppressor gene(s) on murine chromosome 12 and human chromosome 14q32. We previously described that putative tumor suppressor gene(s) might reside between D12Mit53 and D12Mit233. We analyzed three genes, Tcl1, Yy1 and Tnfalphaip2, which had been mapped around the region, as the candidates in radiation lymphomagenesis of (BALB/c x MSM/Ms)F1 hybrid mice. The locus order and distances of the three genes and microsatellite loci were estimated as follows: [centromere] - Tcl1-(> or =0.085 cM)-D12Mit50-(0.085 cM)D12Mit132-(1.96 cM)D12Mit122-(0.085 cM)D12Mit53-(1.37 cM)-[D12Mit233,D12Mit279,Yy1]-(0.085 cM)-D12Mit181-(> or =0.17 cM)-Tnfalphaip2 - [telomere]. Allele losses at Tcl1, Yy1 genes and D12Mit233 were observed in 94(45%), 143(68%) and 147(70%) of 210 lymphomas, respectively. In semi-quantitative analysis of Yy1 mRNA levels by RT-PCR, kinetics of the yield of the Yy1-cDNA-specific PCR products showed almost the same profiles among thymic lymphomas with allelic loss at Yy1, lymphomas with both alleles retained and normal thymus. These results suggest that Tcl1, Yy1 and Tnfalphaip2 genes are not predominantly involved in radiation lymphomagenesis of mice. In further analysis of the common allelic loss region, we found new loci, Y152pR1 and Y184pR2, from YACs which located in the hot region between D12Mit53 and D12Mit233, and the highest frequency of allelic loss (71%) was observed at the Y184pR2 locus. The LOH patterns of individual lymphomas suggest that putative tumor suppressor gene(s) lies between Y152pR1 and Y184pR2.
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Genes Supresores de Tumor/genética , Pérdida de Heterocigocidad , Linfoma/genética , Neoplasias Inducidas por Radiación/genética , Proteínas Proto-Oncogénicas , Animales , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Factores de Unión al ADN Específico de las Células Eritroides , Femenino , Haplotipos , Linfoma/etiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Repeticiones de Microsatélite/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recombinación Genética/genética , Testículo/metabolismo , Timo/metabolismo , Timo/patología , Timo/efectos de la radiación , Factores de Transcripción/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Transcripción YY1RESUMEN
Topical nicotinamide (niacinamide) has demonstrable preventive activity against photocarcinogenesis in mice. To better understand how this vitamin prevents ultraviolet (UV) carcinogenesis, we tested systemic administration of another form of the vitamin, niacin, and its capacity to elevate cutaneous nicotinamide-adenine dinucleotide (NAD) content as well as to decrease photoimmunosuppression and photocarcinogenesis. BALB/cAnNTacfBR mice were fed the AIN-76A diet supplemented with 0%, 0.1%, 0.5%, or 1.0% niacin throughout the experiment. UV irradiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 22 weeks in the carcinogenesis experiments, yielding a total cumulative dose of approximately 1.41 x 10(6) Jm-2 of UV-B radiation. Dietary supplementation with 0.1%, 0.5%, or 1.0% niacin reduced the control incidence of skin cancer from 68% to 60%, 48%, and 28%, respectively, at 26.5 weeks after the first UV treatment. Two potential mechanisms by which niacin prevents tumor formation were identified. Photoimmunosuppression, critical for photocarcinogenesis, is measured by a passive transfer assay. Syngeneic, antigenic tumor challenges grew to an average of 91.6 +/- 19.7, 79.8 +/- 11.5, 41.9 +/- 11.7, or 13.2 +/- 4.1 mm2 in naive recipients of splenocytes from UV-irradiated mice treated with 0%, 0.1%, 0.5%, or 1.0% niacin supplementation, respectively, demonstrating niacin prevention of immunosuppression. Niacin supplementation elevated skin NAD content, which is known to modulate the function of DNA strand scission surveillance proteins p53 and poly(ADP-ribose) polymerase, two proteins critical in cellular responses to UV-induced DNA damage. These results clearly demonstrate a dose-dependent preventive effect of oral niacin on photocarcinogenesis and photoimmunosuppression and establish the capacity of oral niacin to elevate skin NAD levels.
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Anticarcinógenos/uso terapéutico , Terapia de Inmunosupresión , Neoplasias Inducidas por Radiación/prevención & control , Niacina/uso terapéutico , Neoplasias Cutáneas/prevención & control , Administración Oral , Animales , Anticarcinógenos/administración & dosificación , Antígenos de Neoplasias/metabolismo , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Inmunización Pasiva , Ratones , Ratones Endogámicos BALB C , NAD/metabolismo , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/inmunología , Niacina/administración & dosificación , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Organismos Libres de Patógenos Específicos , Rayos Ultravioleta/efectos adversosRESUMEN
The objective of this study was to investigate the incidence of overexpression of TP53 (formerly known as p53) in osteosarcomas occurring after treatment of rabbit mandibles with high-dose external-beam radiation. As part of a protocol investigating hyperbaric oxygen treatment for osteoradionecrosis, 102 female New Zealand-White rabbits underwent mandibular radiation treatments with a total dose of 64 Gy in 20 treatment fractions. Twelve animals died during irradiation, leaving 90 animals at risk for tumor development. These animals were divided into one control group and 12 other groups each treated with different schedules of postirradiation hyperbaric oxygen. All animals were sacrificed after the hyperbaric oxygen treatment, approximately 8 months after completion of irradiation. Seventeen of the 90 animals that survived after irradiation developed high-grade osteosarcomas, for a 19% incidence of malignancy. Tumor sizes ranged from 1-4 cm. Immunohistochemistry staining of the 17 tumors detected a 59% overall incidence of TP53 overexpression. There was no correlation between the intensity of hyperbaric oxygen treatment and development of osteosarcoma. The high incidence and short interval of development of osteosarcoma suggest that the study animals may have had a genetic predisposition to radiation-induced osteosarcoma. Additionally, our data provide further evidence that TP53 mutations may play an important role in radiation-induced osteosarcoma.
Asunto(s)
Genes p53 , Neoplasias Mandibulares/genética , Neoplasias Inducidas por Radiación/genética , Osteosarcoma/genética , Animales , Femenino , Expresión Génica , Oxigenoterapia Hiperbárica , Inmunohistoquímica , Neoplasias Mandibulares/etiología , Neoplasias Mandibulares/metabolismo , Mutación , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/metabolismo , Osteorradionecrosis/etiología , Osteorradionecrosis/terapia , Osteosarcoma/etiología , Osteosarcoma/metabolismo , Conejos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
In the present study, administration of green tea to SKH-1 mice, via the drinking fluid, was found to significantly reduce the incidence and volume of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated with green tea in their drinking water, were collected and examined for the presence of mutations in the p53 gene. Polymerase chain reaction products from p53 exons 5-8 were screened by single-strand conformation polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors contained nine p53 mutations, with four in exon 5 and five in exon 8. In contrast, nine of 32 UVB-induced tumors in mice treated with green tea contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These results were further corroborated by p53 immunohistochemistry. The most frequent mutations were C-->T or T-->C transitions, which are consistent with the genetic alterations caused by UVB exposure. Interestingly, mutations found in exon 6 of the p53 gene occurred only in tumors from the UVB/green tea group. Thus, the tumors observed in UVB/green-tea-treated mice have a different exon distribution of p53 mutations than tumors obtained from mice treated with UVB alone.
Asunto(s)
Anticarcinógenos/uso terapéutico , Genes p53 , Mutación , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/prevención & control , Té , Rayos Ultravioleta/efectos adversos , Animales , Carcinoma de Células Grandes/etiología , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/prevención & control , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/prevención & control , Codón , Exones , Femenino , Inmunohistoquímica , Ratones , Ratones Pelados , Neoplasias Inducidas por Radiación/etiología , Reacción en Cadena de la Polimerasa , Neoplasias Cutáneas/etiología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Ionizing radiation is the exogenous agent best proven to induce breast cancer. c-erbB2/neu amplification and overexpression are known to occur in breast cancer and are correlated with aggressive tumor growth and poor prognosis. We have developed simian virus 40-immortalized cell lines from normal human breast epithelial cells (HBECs) with luminal and stem-cell characteristics. In this study, we examined whether x-rays and a mutated neu oncogene are capable of inducing tumorigenicity in these cells. The results indicated that x-rays were effective in converting immortal non-tumorigenic HBECs to weakly tumorigenic cells that then could be transformed to highly tumorigenic cells by the neu oncogene. The in vitro growth of these tumorigenic cells was significantly faster than that of the parental non-tumorigenic cells in growth factor- and hormone-supplemented or -depleted media. The neu oncogene, however, had no tumorigenic effect on immortal non-tumorigenic cells. The expression of p185(c-erb82/neu) was elevated in neu-transduced immortal or weakly tumorigenic cell lines. However, only in the latter was p185(c-erbB2/neu) found to be phosphorylated at tyrosine residues. Thus, x-rays appear to induce a genetic alteration that confers weak tumorigenicity on immortal HBECs and interacts with p185(c-erbB2/neu) directly or indirectly to give rise to fast-growing tumors.
Asunto(s)
Mama/efectos de la radiación , Transformación Celular Neoplásica/efectos de la radiación , Genes erbB-2 , Neoplasias Mamarias Experimentales/genética , Neoplasias Inducidas por Radiación/genética , Procesamiento Proteico-Postraduccional , Receptor ErbB-2/metabolismo , Animales , Mama/citología , División Celular , Línea Celular Transformada , Transformación Celular Neoplásica/genética , Transformación Celular Viral , Senescencia Celular , Cocarcinogénesis , Células Epiteliales/efectos de la radiación , Femenino , Amplificación de Genes , Humanos , Neoplasias Mamarias Experimentales/etiología , Ratones , Ratones Desnudos , Neoplasias Inducidas por Radiación/metabolismo , Fosforilación , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/fisiología , Virus 40 de los Simios/fisiologíaRESUMEN
The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations.
Asunto(s)
Partículas alfa/efectos adversos , ADN de Neoplasias/genética , Genes p53/efectos de la radiación , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Minería , Neoplasias Inducidas por Radiación/genética , Enfermedades Profesionales/genética , Mutación Puntual , Dióxido de Torio/efectos adversos , Anciano , Anciano de 80 o más Años , Codón/genética , Medios de Contraste/efectos adversos , Análisis Mutacional de ADN , Exones/genética , Alemania/epidemiología , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/etiología , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/etiología , Polimorfismo de Longitud del Fragmento de Restricción , Radón/efectos adversos , Fumar/efectos adversos , Fumar/epidemiología , Fumar/genética , Uranio/efectos adversosAsunto(s)
Genes p53/efectos de la radiación , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Minería , Mutación , Neoplasias Inducidas por Radiación/genética , Enfermedades Profesionales/etiología , Enfermedades Profesionales/genética , Radón/efectos adversos , Uranio , Carcinoma de Células Grandes/etiología , Carcinoma de Células Grandes/genética , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Codón/efectos de la radiación , Exones/efectos de la radiación , Alemania , HumanosAsunto(s)
Genes p53 , Minería , Mutación , Neoplasias Inducidas por Radiación/genética , Enfermedades Profesionales/genética , Radón/efectos adversos , Esterigmatocistina/efectos adversos , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Humanos , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Neoplasias Inducidas por Radiación/etiología , Enfermedades Profesionales/etiología , UranioRESUMEN
Mutations in gene p53 are the most common defects in lung cancer and may be a pathway through which environmental carcinogens initiate cancer. We investigated p53 mutations in lung cancers from uranium miners with high radon exposure. 16 (31%) of 52 large-cell and squamous-cell cancers from miners contained the same AGG to ATG transversion at codon 249, including cancers from 3 or 5 miners who had never smoked. This specific mutation has been reported in only 1 of 241 published p53 mutations from lung cancers. The codon 249 mutation may be a marker for radon-induced lung cancer.