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1.
J Infect Dis ; 219(3): 400-409, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30307559

RESUMO

Background: Oral Epstein-Barr virus (EBV) status reflects host EBV activity and potentially links to EBV-associated diseases, however, factors influencing oral EBV loads or reactivation, such as environmental exposures or host factors, are not fully understood. Methods: A 2-stage, multicenter, cross-sectional study of 6558 subjects from 21 administrative cities of southern China and 3 populations from representative geographical areas in China (referred to as the south, north, and northeastern populations) was performed. The relationships between demographical factors and environmental exposures to EBV loads were analyzed by logistic regression models. Results: Current smoking, with a dose-response effect, was found to be strongly associated with higher oral EBV loads in the pooled data, with an odds ratio of 1.58 (95% confidence interval, 1.39-1.79), as well as in each of the separate populations. The odds ratio increased to 3.06 when current smokers in southern China were compared to never smokers in northern China. Additionally, higher oral EBV loads tended to be detected in older participants, male participants, and participants in southern China. Conclusions: This study provided evidence linking the effect of host-environmental factors, particularly smoking, to oral EBV activity. It could strengthen our understanding of the possible causal roles of EBV-related diseases, which may help to prevent or mitigate EBV-associated diseases.


Assuntos
DNA Viral , Demografia , Exposição Ambiental , Herpesvirus Humano 4/genética , Boca/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos Transversais , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , População , Análise de Regressão , Fumar , Carga Viral , Adulto Jovem
2.
Cancer Med ; 7(7): 3453-3464, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29905022

RESUMO

The link of nasopharyngeal carcinoma (NPC) with Epstein-Barr virus (EBV) has been established for decades. Although an abnormal high level of EBV sero-antibody spectrum and cell-free circulating EBV DNA loads were exhibited in NPC patients, oral EBV DNA loads, which are primarily responsible for the EBV transmission, has not been previously studied in NPC patients. We conducted an epidemiological study to measure the oral EBV loads, viral components, and the relationship with the serum antibody titers in a large case-control population (968 cases and 1656 controls) and a family-based population (91 cases and 165 unaffected family members). EBV DNA loads were detected by quantitative PCR approach targeting the BamHI-W region. Although a large individualized variation existed, we still observed a decreased oral EBV DNA loads in the population of NPC patients compared to that of healthy controls (ORs were 1.00, 0.69, 0.62, 0.33 classified by the quartiles of viral loads, Ptrend  < .001) and family members. In contrast, the elevated levels of oral EBV loads were present in asymptomatic males and elders, suggesting a different important source for EBV transmission. Notably, oral EBV loads were inversely associated with serum antibody titers of VCA-IgA, EA-IgA (All Ptrend  < .001) in the cases but not in the controls. Our study provides the first epidemiological data of oral EBV loads and viral components in NPC patients and controls in the highest risk area of Southern China, indicating that NPC status is unlikely to be an important determinant of EBV transmission.

3.
Int J Oncol ; 50(2): 622-630, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28035363

RESUMO

Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC.


Assuntos
Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Apoptose , Sítios de Ligação , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/química , Camundongos , Transplante de Neoplasias , Estabilidade Proteica , Edição de RNA , Transdução de Sinais
4.
Am J Hum Genet ; 98(4): 709-27, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27058444

RESUMO

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Variações do Número de Cópias de DNA , Carcinoma de Células Escamosas do Esôfago , Exoma , Proteína de Domínio de Morte Associada a Fas/genética , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/genética , Prognóstico , Seleção Genética , Transativadores/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Cell Mol Med ; 20(7): 1219-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26893171

RESUMO

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta-analysis of all available case-control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448-2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large-scale studies considering gene-environment interactions and functional research should be conducted to further investigate this association.


Assuntos
Predisposição Genética para Doença , Proteína da Hemocromatose/genética , Mutação/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Razão de Chances , Viés de Publicação , Fatores de Risco
6.
Sci Rep ; 5: 11955, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26148476

RESUMO

Aberrant expression of receptor interacting protein kinase 4 (RIPK4), a crucial regulatory protein of Wnt/ß-catenin signaling, has recently been reported to be involved in several cancers. Here, we report the potential clinical implication and biological functions of RIPK4 in cervical squamous cell carcinoma (CSCC). One hundred and ninety-eight CSCC cases, 109 low-grade squamous intraepithelial lesions (LSILs), 141 high-grade squamous intraepithelial lesions (HSILs) and 63 chronic cervicitis were collected. The expression of RIPK4 was detected by immunohistochemistry (IHC), and its clinical value and oncogenic functions were further assessed. RIPK4 expression increased significantly with disease progression from 3.2% in chronic cervicitis, 19.3% in LSILs and 85.1% in HSILs to 94.4% in CSCCs (P < 0.001). Moreover, RIPK4 may serve as a useful biomarker to distinguish HSIL from chronic cervicitis/LSIL, which are two different clinical types for therapeutic procedures, with a high sensitivity and specificity (85.1% and 86.6%, respectively) and the performance improved when combined with p16(INK4a). Further, RIPK4 overexpression was associated with overall (HR = 2.085, P = 0.038) and disease-free survival (HR = 1.742, P = 0.037). Knockdown of RIPK4 reduced cell migration and invasion via inhibition of Vimentin, MMP2 and Fibronectin expression in cervical cancer cells. RIPK4 might act as a potential diagnostic and independent prognostic biomarker for CSCC patients.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Fibronectinas/química , Fibronectinas/metabolismo , Humanos , Imuno-Histoquímica , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Microscopia Confocal , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Vimentina/química , Vimentina/metabolismo
7.
Sci Rep ; 4: 6159, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25146845

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies.


Assuntos
Alelos , Predisposição Genética para Doença , Linfoma não Hodgkin/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Razão de Chances , Viés de Publicação , RNA Mensageiro/genética , Risco
8.
Tumour Biol ; 35(4): 3905-15, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24347488

RESUMO

Numerous epidemiological studies have been conducted to investigate the association between Xeroderma pigmentosum complementation group D (XPD) Asp312Asn (rs1799793 G > A) and Lys751Gln (rs13181 A > C) polymorphisms and bladder cancer risk; however, the conclusions remain controversial. With this in mind, we performed this meta-analysis with 11 studies including 3,797 cases and 5,094 controls for Asp312Asn and 21 studies including 6,360 cases and 7,894 controls for Lys751Gln polymorphism. We searched available literatures from PubMed, Embase, and CBM databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. Moreover, to validate biological plausibility of our findings, the effects of these two polymorphisms on XPD gene expression within three ethnicities was determine by gene expression analysis based on imputed genotypes from HapMap. Overall, the variant allele of Asp312Asn polymorphism was associated with an increased risk of bladder cancer (Asn/Asn vs. Asp/Asp: OR = 1.51, 95% CI = 1.19-1.91; Asp/Asn vs. Asp/Asp: OR = 1.23, 95% CI = 1.12-1.35; recessive model: OR = 1.33, 95% CI = 1.10-1.61; dominant model: OR = 1.32, 95% CI = 1.14-1.52; and allele comparing: OR = 1.26, 95% CI = 1.11-1.42). We found the Lys751Gln was associated with increased bladder cancer risk only under the recessive model (OR = 1.14, 95% CI = 1.01-1.29). Stratification analyses demonstrated an increased risk for Asians and hospital-based studies under all genetic models while only under the dominant model for Caucasians as to the Asp312Asn polymorphism and for Caucasians under the recessive model as to the Lys751Gln polymorphism. We also found the Asp312Asn polymorphism can significantly influence mRNA expression levels among Asians and Caucasians, and the Lys751Gln polymorphism has a similar effect for Caucasians. Despite some limitations, this meta-analysis suggests that polymorphisms in XPD gene may contribute to bladder cancer susceptibility. These findings need further validation by large well-designed prospective studies.


Assuntos
Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias da Bexiga Urinária/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Humanos , Viés de Publicação , Risco , Neoplasias da Bexiga Urinária/etiologia
9.
Cancer Sci ; 104(12): 1675-82, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24118380

RESUMO

Long non-coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well-known LncRNA, has been found to play important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time-polymerase chain reaction (qPCR). WIF-1 playing an important role in Wnt/ß-catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF-1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF-1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/ß-catenin signaling pathway. This newly identified HOTAIR/WIF-1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Wnt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Metilação de DNA , Neoplasias Esofágicas/genética , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Receptores CXCR/metabolismo , Proteínas Repressoras/biossíntese , Regulação para Cima , Via de Sinalização Wnt , beta Catenina/metabolismo
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