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1.
Cancer Sci ; 115(6): 1808-1819, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38572512

RESUMO

Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.


Assuntos
DNA Polimerase Dirigida por DNA , Metilnitrosoureia , Mutagênese , Nucleotidiltransferases , Neoplasias do Timo , Animais , Camundongos , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Sequenciamento do Exoma , Linfoma/genética , Linfoma/induzido quimicamente , Linfoma/patologia , Metilnitrosoureia/toxicidade , Camundongos Transgênicos , Mutação , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Neoplasias do Timo/genética , Neoplasias do Timo/induzido quimicamente , Neoplasias do Timo/patologia
2.
Carcinogenesis ; 44(1): 105-118, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36546734

RESUMO

Age at exposure is a major modifier of radiation-induced carcinogenesis. We used mouse models to elucidate the mechanism underlying age-related susceptibility to radiation-induced tumorigenesis. Radiation exposure in infants was effective at inducing tumors in B6/B6-Chr18MSM-F1 ApcMin/+ mice. Loss of heterozygosity analysis revealed that interstitial deletion may be considered a radiation signature in this model and tumor number containing a deletion correlated with the susceptibility to radiation-induced tumorigenesis as a function of age. Furthermore, in Lgr5-eGFP-ires-CreERT2; Apcflox/flox mice, deletions of both floxed Apc alleles in Lgr5-positive stem cells in infants resulted in the formation of more tumors than in adults. These results suggest that tumorigenicity of Apc-deficient stem cells varies with age and is higher in infant mice. Three-dimensional immunostaining analyses indicated that the crypt architecture in the intestine of infants was immature and different from that in adults concerning crypt size and the number of stem cells and Paneth cells per crypt. Interestingly, the frequency of crypt fission correlated with the susceptibility to radiation-induced tumorigenesis as a function of age. During crypt fission, the percentage of crypts with lysozyme-positive mature Paneth cells was lower in infants than that in adults, whereas no difference in the behavior of stem cells or Paneth cells was observed regardless of age. These data suggest that morphological dynamics in intestinal crypts affect age-dependent susceptibility to radiation-induced tumorigenesis; oncogenic mutations in infant stem cells resulting from radiation exposure may acquire an increased proliferative potential for tumor induction compared with that in adults.


Assuntos
Intestinos , Células-Tronco , Camundongos , Animais , Intestinos/patologia , Células-Tronco/patologia , Carcinogênese/genética , Carcinogênese/patologia , Mucosa Intestinal
3.
Radiat Res ; 197(4): 332-349, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34958666

RESUMO

We present time and dose dependencies for the formation of 53BP1 and γH2AX DNA damage repair foci after chronic radiation exposure at dose rates of 140, 250 and 450 mGy/day from 3 to 96 h, in human and mouse repair proficient and ATM or DNA-PK deficient repair compromised cell models. We describe the time/dose-response curves using a mathematical equation which contains a linear component for the induction of DNA damage repair foci after irradiation, and an exponential component for their resolution. We show that under conditions of chronic irradiation at low and medium dose rates, the processes of DNA double-strand breaks (DSBs) induction and repair establish an equilibrium, which in repair proficient cells manifests as a plateau-shaped dose-response where the plateau is reached within the first 24 h postirradiation, and its height is proportionate to the radiation dose rate. In contrast, in repair compromised cells, where the rate of repair may be exceeded by the DSB induction rate, DNA damage accumulates with time of exposure and total absorbed dose. In addition, we discuss the biological meaning of the observed dependencies by presenting the frequency of micronuclei formation under the same irradiation conditions as a marker of radiation-induced genomic instability. We believe that the data and analysis presented here shed light on the kinetics of DNA repair under chronic radiation and are useful for future studies in the low-to-medium dose rate range.


Assuntos
Reparo do DNA , Histonas , Animais , DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Fibroblastos/efeitos da radiação , Histonas/metabolismo , Cinética , Camundongos
4.
Redox Rep ; 26(1): 160-169, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34435550

RESUMO

Objectives: High dose-rate ionizing radiation (IR) causes severe DSB damage, as well as reactive oxygen species (ROS) accumulation and oxidative stress. However, it is unknown what biological processes are affected by low dose-rate IR; therefore, the molecular relationships between mitochondria changes and oxidative stress in human normal cells was investigated after low dose-rate IR.Methods: We compared several cellular response between high and low dose-rate irradiation using cell survival assay, ROS/RNS assay, immunofluorescence and western blot analysis.Results: Reduced DSB damage and increased levels of ROS, with subsequent oxidative stress responses, were observed in normal cells after low dose-rate IR. Low dose-rate IR caused several mitochondrial changes, including morphology mass, and mitochondrial membrane potential, suggesting that mitochondrial damage was caused. Although damaged mitochondria were removed by mitophagy to stop ROS leakage, the mitophagy-regulatory factor, PINK1, was reduced following low dose-rate IR. Although mitochondrial dynamics (fission/fusion events) are important for the proper mitophagy process, some mitochondrial fusion factors decreased following low dose-rate IR.Discussion: The dysfunction of mitophagy pathway under low dose-rate IR increased ROS and the subsequent activation of the oxidative stress response.


Assuntos
Mitocôndrias , Estresse Oxidativo , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Mitofagia , Espécies Reativas de Oxigênio/metabolismo
5.
Radiat Res ; 196(1): 40-54, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33857310

RESUMO

Low-dose-rate radiation exposures and their associated cancer risk are an important concern for radiation protection today. Nevertheless, there is almost no data concerning DNA damage at dose rates below 0.1 mGy/min. In this study, we investigated the formation of DNA damage repair foci under chronic low-dose-rate irradiation relative to acute high-dose-rate irradiation and assessed the magnitude of the dose-rate effect. Four human and four mouse normal fibroblast cell models from different organs were subjected to gamma irradiation at 0.096 mGy/min or 0.81 Gy/min, and dose-response curves were established for the dose range from 0.1 to 0.8 Gy. The results indicate that prolonged low-dose-rate exposures cause modestly increased levels of DNA repair foci, with a strongly supralinear dose-response relationship, where 40-70% of the radiation effect at 1 Gy was already present at the total dose of 0.1 Gy. Thus, compared to acute irradiation, low-dose-rate exposure was 6-9 times less efficient at a total dose of 0.1 Gy, and 10-20 times less efficient at 1 Gy. Comparison between cell models revealed a certain correlation between the presence of persistent, above-background foci at 48 h after irradiation and the sensitivity to low-dose-rate radiation, suggesting that repair capacity plays an important role in the cellular response to chronic irradiation. Given the findings reported here, we propose that establishing detailed dose-response curves and accounting for the repair rates of different cell models are essential steps in elucidating dose-rate effects.


Assuntos
Quebras de DNA de Cadeia Dupla , Fibroblastos/efeitos da radiação , Raios gama , Animais , Células Cultivadas , Relação Dose-Resposta à Radiação , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
6.
Genes Environ ; 42: 9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161626

RESUMO

Translesion synthesis (TLS) is an error-prone pathway required to overcome replication blockage by DNA damage. Aberrant activation of TLS has been suggested to play a role in tumorigenesis by promoting genetic mutations. However, the precise molecular mechanisms underlying TLS-mediated tumorigenesis in vivo remain unclear. Rev1 is a member of the Y family polymerases and plays a key role in the TLS pathway. Here we introduce the existing to date Rev1-mutated mouse models, including the Rev1 transgenic (Tg) mouse model generated in our laboratory. We give an overview of the current knowledge on how different disruptions in Rev1 functions impact mutagenesis and the suggested molecular mechanisms underlying these effects. We summarize the available data from ours and others' in vivo studies on the role of Rev1 in the initiation and promotion of cancer, emphasizing how Rev1-mutated mouse models can be used as complementary tools for future research.

7.
Cell Death Dis ; 11(2): 145, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094325

RESUMO

Compelling evidence has demonstrated the potential functions of circular RNAs (circRNAs) in breast cancer (BC) tumorigenesis. Nevertheless, the underlying mechanism by which circRNAs regulate BC progression is still unclear. The purpose of present research was to investigate the novel circRNA circRNF20 (hsa_circ_0087784) and its role in BC. CircRNA microarray sequencing revealed that circRNF20 was one of the upregulated transcripts in BC samples. Increased circRNF20 level predicted the poor clinical outcome in BC specimens. Functionally, circRNF20 promoted the proliferation and Warburg effect (aerobic glycolysis) of BC cells. Mechanistically, circRNF20 harbor miR-487a, acting as miRNA sponge, and then miR-487a targeted the 3'-UTR of hypoxia-inducible factor-1α (HIF-1α). Moreover, HIF-1α could bind with the promoter of hexokinase II (HK2) and promoted its transcription. In conclusion, this finding illustrates the vital roles of circRNF20 via the circRNF20/ miR-487a/HIF-1α/HK2 axis in breast cancer progress and Warburg effect, providing an interesting insight for the BC tumorigenesis.


Assuntos
Neoplasias da Mama/metabolismo , Hexoquinase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Efeito Warburg em Oncologia , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células MCF-7 , Masculino , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética , Transdução de Sinais , Transcrição Gênica
8.
J Radiat Res ; 60(6): 768-779, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31665386

RESUMO

Chronic inflammation is a common denominator linking a wide range of health conditions, including tissue response to radiation exposure. This pilot study investigates whether inflammatory cytokines-interleukins IL-6, -8, -10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNFα)-can be used as early biomarkers of radiation-induced adverse health effects in occupationally exposed individuals. The study included 33 workers externally exposed to gamma radiation from the nuclear industry with cumulated doses from 0.11 to 190 mSv and 42 non-exposed controls of comparable age and socio-economic status. IL-6, IL-8, MCP-1, TNFα and IL-10 were analyzed by enzyme-linked assay (ELISA) in blood plasma samples. Total antioxidant status (TAS) of blood plasma was determined by a colorimetric assay. The radiation-exposed and control groups measured significantly different levels of MCP-1, TNFα and IL-10. Seventy-five percent of radiation workers had either high MCP-1 levels or low IL-10 levels and 30% had all three cytokines dysregulated. Approximately 50% of workers showed upregulated antioxidant status, which appeared to compensate the pro-inflammatory cytokine shift in these individuals. In contrast, only 2% of the control subjects were found to have three dysregulated cytokines, and all of them measured within the normal TAS range. The present study may represent an important step towards the establishment of a reliable set of biomarkers for health-risk estimation in population cohorts exposed to low radiation doses.


Assuntos
Raios gama , Inflamação/patologia , Centrais Nucleares , Exposição Ocupacional/análise , Exposição à Radiação/análise , Adulto , Antioxidantes/metabolismo , Estudos de Casos e Controles , Citocinas/sangue , Relação Dose-Resposta à Radiação , Humanos , Hipertensão/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade
9.
Saudi J Biol Sci ; 26(1): 178-182, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30622424

RESUMO

Mammotome-an ultrasound guided vacuum-assisted breast biopsy (VABB) device, has proved beneficial to the treatment of benign breast lesions. The aim of this study is to analyze the characteristics of ultrasound images of residual cavity and the changes in ultrasound images at follow-up at different intervals after the excision of benign breast lesions by Mammotome® biopsy system. A series of 247 consecutive 8-gauge Mammotome® procedures were performed under ultrasound guidance and multivariate analysis was conducted. We found fibroadenoma and adenomatosis are appeared to be the most common pathological manifestations. Follow-up by ultrasonography at an interval of one month after excision of benign breast lesions by 8-gauge vacuum-assisted Mammotome® biopsy system, is not reliable due to the residual cavity formation. A follow-up schedule starting from at least 3 months after resection is highly recommended.

10.
Carcinogenesis ; 38(5): 570-578, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28498946

RESUMO

Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels are associated with DNA damage induced cytotoxicity and mutagenicity. However, it remains unclear whether deregulated Rev1 expression triggers or promotes tumorigenesis in vivo. In this study, we generated a novel Rev1-overexpressing transgenic (Tg) mouse and characterized its susceptibility to tumorigenesis. Using a small intestinal tumor model induced by N-methyl-N-nitrosourea (MNU), we found that transgenic expression of Rev1 accelerated intestinal adenoma development in proportion to the Rev1 expression level; however, overexpression of Rev1 alone did not cause spontaneous development of intestinal adenomas. In Rev1 Tg mice, MNU-induced mutagenesis was elevated, whereas apoptosis was suppressed. The effects of hREV1 expression levels on the cytotoxicity and mutagenicity of MNU were confirmed in the human cancer cell line HT1080. These data indicate that dysregulation of cellular Rev1 levels leads to the accumulation of mutations and suppression of cell death, which accelerates the tumorigenic activities of DNA-damaging agents.


Assuntos
Adenoma/etiologia , Apoptose/genética , Carcinógenos/toxicidade , Expressão Gênica , Neoplasias Intestinais/etiologia , Nucleotidiltransferases/genética , Mutação Puntual , Adenoma/patologia , Alelos , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Dano ao DNA , DNA Polimerase Dirigida por DNA , Modelos Animais de Doenças , Progressão da Doença , Frequência do Gene , Genótipo , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Carga Tumoral
11.
Int J Radiat Biol ; 92(2): 87-93, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26634771

RESUMO

Purpose Radiation exposure, besides the risk of cancer, may also increase the risk of non-cancer diseases, including cardiovascular disease (CVD). This study investigates whether the soluble form of the ST2 receptor (sST2), an emerging prognostic marker in patients with CVD, can be used to monitor the CVD risk in individuals occupationally exposed to radiation. Materials and methods sST2 in blood plasma from 69 individuals, 45 workers from the nuclear industry and 24 controls, was analyzed using enzyme-linked assay (ELISA). Total antioxidant status (TAS) of blood plasma and levels of reactive oxygen species (ROS) in lymphocytes were determined by colorimetric and fluorescence assays. Results The data suggest a 5-fold increase in the number of subjects with sST2 levels above the clinical threshold and a 10-fold increase in the number of subjects with TAS levels outside the reference range in the exposed group when compared to the group of non-exposed individuals. The strongest up-regulation of TAS was measured in the group of younger workers with cumulative doses not exceeding 50 mSv. Conclusion The present study may represent an initial step towards the establishment of sST2 as a biomarker for CVD risk estimation in the context of radiation exposure.


Assuntos
Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Exposição Ocupacional/análise , Exposição à Radiação/análise , Espécies Reativas de Oxigênio/sangue , Receptores de Superfície Celular/sangue , Absorção de Radiação , Adulto , Biomarcadores/sangue , Células Cultivadas , Relação Dose-Resposta à Radiação , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Masculino , Pessoa de Meia-Idade , Doses de Radiação
12.
Lancet ; 386(9992): 469-78, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26251392

RESUMO

Late-onset effects of exposure to ionising radiation on the human body have been identified by long-term, large-scale epidemiological studies. The cohort study of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki (the Life Span Study) is thought to be the most reliable source of information about these health effects because of the size of the cohort, the exposure of a general population of both sexes and all ages, and the wide range of individually assessed doses. For this reason, the Life Span Study has become fundamental to risk assessment in the radiation protection system of the International Commission on Radiological Protection and other authorities. Radiation exposure increases the risk of cancer throughout life, so continued follow-up of survivors is essential. Overall, survivors have a clear radiation-related excess risk of cancer, and people exposed as children have a higher risk of radiation-induced cancer than those exposed at older ages. At high doses, and possibly at low doses, radiation might increase the risk of cardiovascular disease and some other non-cancer diseases. Hereditary effects in the children of atomic bomb survivors have not been detected. The dose-response relation for cancer at low doses is assumed, for purposes of radiological protection, to be linear without a threshold, but has not been shown definitively. This outstanding issue is not only a problem when dealing appropriately with potential health effects of nuclear accidents, such as at Fukushima and Chernobyl, but is of growing concern in occupational and medical exposure. Therefore, the appropriate dose-response relation for effects of low doses of radiation needs to be established.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Acidente Nuclear de Fukushima , Neoplasias Induzidas por Radiação/epidemiologia , Guerra Nuclear , Liberação Nociva de Radioativos , Fatores Etários , Acidente Nuclear de Chernobyl , Relação Dose-Resposta à Radiação , Humanos , Japão/epidemiologia , Armas Nucleares , Lesões por Radiação/epidemiologia , Sobreviventes , Fatores de Tempo , Ucrânia/epidemiologia
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