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Head and neck squamous cell carcinoma (HNSC) exhibits genetic heterogeneity in etiologies, tumor sites, and biological processes, which significantly impact therapeutic strategies and prognosis. While the influence of human papillomavirus on clinical outcomes is established, the molecular subtypes determining additional treatment options for HNSC remain unclear and inconsistent. This study aims to identify distinct HNSC molecular subtypes to enhance diagnosis and prognosis accuracy. In this study, we collected three HNSC microarrays (n = 306) from the Gene Expression Omnibus (GEO), and HNSC RNA-Seq data (n = 566) from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes (DEGs) and validate our results. Two scoring methods, representative score (RS) and perturbative score (PS), were developed for DEGs to summarize their possible activation functions and influence in tumorigenesis. Based on the RS and PS scoring, we selected candidate genes to cluster TCGA samples for the identification of molecular subtypes in HNSC. We have identified 289 up-regulated DEGs and selected 88 genes (called HNSC88) using the RS and PS scoring methods. Based on HNSC88 and TCGA samples, we determined three HNSC subtypes, including one HPV-associated subtype, and two HPV-negative subtypes. One of the HPV-negative subtypes showed a relationship to smoking behavior, while the other exhibited high expression in tumor immune response. The Kaplan-Meier method was used to compare overall survival among the three subtypes. The HPV-associated subtype showed a better prognosis compared to the other two HPV-negative subtypes (log rank, p = 0.0092 and 0.0001; hazard ratio, 1.36 and 1.39). Additionally, within the HPV-negative group, the smoking-related subgroup exhibited worse prognosis compared to the subgroup with high expression in immune response (log rank, p = 0.039; hazard ratio, 1.53). The HNSC88 not only enables the identification of HPV-associated subtypes, but also proposes two potential HPV-negative subtypes with distinct prognoses and molecular signatures. This study provides valuable strategies for summarizing the roles and influences of genes in tumorigenesis for identifying molecular signatures and subtypes of HNSC.
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Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinogênese , Transformação Celular Neoplásica , Papillomavirus HumanoRESUMO
A new uranyl silicate, K2Ca4[(UO2)(Si2O7)2], with a 1D chain structure has been synthesized from a solution of mixed alkali- and alkaline-earth-metal cations under hydrothermal conditions at 550 °C and 1400 bar and characterized by single-crystal X-ray diffraction and photoluminescence spectroscopy. It crystallizes in the triclinic space group P1Ì (No. 2) with a = 6.6354(2) Å, b = 6.6791(2) Å, c = 9.6987(3) Å, α = 98.324(2)°, ß = 93.624(2)°, γ = 112.310(2)°, and Z = 1. Its crystal structure consists of a 1D chain of uranyl disilicate formed of corner-sharing UO6 tetragonal bipyramids and Si2O7 double groups. The adjacent chains are separated by K(+) and Ca(2+) cations. It is the first example of uranyl silicate with a 1D chain structure.
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Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related death worldwide. The prognosis of HNSCC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis, even at initial diagnosis. Carcinoma-associated fibroblasts (CAFs), a major type of tumour-surrounding stromal cell, generate mediators through which they interact with tumours and contribute to cancer progression. The orchestration between CAFs and cancer cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumour microenvironment on initiation and progression of cancer cells, the major mediator related to CAFs and its underlying mechanism remain unknown. In the present study, we used organotypic culture to investigate CAFs that promote aggressive behaviour of HNSCC cells. Using microarray analysis, we detected abundant expression of interleukin-33 (IL-33) in CAFs and identified IL-33 as a critical mediator in CAF-induced invasiveness. Counteracting IL-33 activity diminished the aggressive phenotype of cancer cells induced by CAFs. Administration of IL-33 promoted cancer cell migration and invasion through induction of epithelial-to-mesenchymal transdifferentiation and increased IL-33 gene expression in cancer cells. In 40 patients with HNSCC, IL-33 expression in CAFs correlated with IL-33 expression in cancer cells. Most cases with a low invasion pattern grading score (IPGS) showed low or no expression of IL-33, whereas most HNSCC cases with high IPGS displayed over-expression of IL-33 in CAFs and cancer cells. High IL-33 expression associated with poor prognosis in terms of nodal metastasis-free survival. These results indicate that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental IL-33 signalling, and suggest that IL-33 is a potential prognostic biomarker that could be considered in therapeutic strategies for the treatment of patients with HNSCC.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Fibroblastos/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Interleucinas/metabolismo , Comunicação Parácrina/fisiologia , Western Blotting , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Interleucina-33 , Estimativa de Kaplan-Meier , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND: Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. METHODS: We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 1997-2007 were analyzed. The case period was defined as the 30 days before admission; the periods 90 to 120 days and 180 to 210 days before admission were used as control periods. Prescribing status of ACE inhibitors and ARBs during the 3 periods was assessed for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) for pneumonia associated with use of ACE inhibitors and ARBs. RESULTS: We identified 10 990 cases of hospitalization for new pneumonia. After adjustment for time-variant confounding factors, pneumonia was not associated with use of ACEI or ARBS: the ORs were 0.99 (95% CI, 0.81-1.21) and 0.96 (0.72-1.28), respectively. No association was seen for cumulative defined daily doses (DDDs), as compared with nonusers, for 0 to 30, 31 to 60, or more than 60 DDDs. The results were found to be robust in sensitivity analysis. CONCLUSIONS: Neither the use nor cumulative dose of ACE inhibitors or ARBs was associated with pneumonia among the Taiwanese general population.
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Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hospitalização/estatística & dados numéricos , Pneumonia/terapia , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudos de Casos e Controles , Estudos Cross-Over , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Risco , Taiwan , Resultado do TratamentoRESUMO
Recent studies have shown that NP (nucleoprotein), which possesses multiple functions in the viral life cycle, is a new potential anti-influenza drug target. NP inhibitors reliably induce conformational changes in NPs, and these changes may confer inhibition of the influenza virus. The six conserved tryptophan residues in NP can be used as an intrinsic probe to monitor the change in fluorescence of the tryptophan residues in the protein upon binding to an NP inhibitor. In the present study, we found that the fluorescence of recombinant NP proteins was quenched following the binding of available NP inhibitors (such as nucleozin) in a concentration- and time-dependent manner, which suggests that the inhibitor induced conformational changes in the NPs. The minimal fluorescence-quenching effect and weak binding constant of nucleozin to the swine-origin influenza virus H1N1pdm09 (SOIV) NP revealed that the SOIV is resistant to nucleozin. We have used the fluorescence-quenching property of tryptophans in NPs that were bound to ligands in a 96-well-plate-based drug screen to assess the ability of promising small molecules to interact with NPs and have identified one new anti-influenza drug, CSV0C001018, with a high SI value. This convenient method for drug screening may facilitate the development of antiviral drugs that target viruses other than the influenza virus, such as HIV and HBV.
Assuntos
Vírus da Influenza A Subtipo H1N1/metabolismo , Nucleoproteínas/antagonistas & inibidores , Espectrometria de Fluorescência , Triptofano/química , Sequência de Aminoácidos , Animais , Antivirais/química , Antivirais/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Dados de Sequência Molecular , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SuínosRESUMO
BACKGROUND: To clarify the efficacy of grape seed procyanidin (GSP) on antiproliferative effects related to p53 functional status of oral squamous cell carcinoma (OSCC) for its chemoadjuvant potential. METHODS: We used GSP to investigate SCC-25 cells with wild-type p53 gene and OEC-M1 cells with mutant p53 gene for the assessment of antiproliferative effects including cell viability, cell cycle, apoptosis, migration and invasion potential, and alterations of associated oncoproteins involved in cellular and molecular events. RESULTS: The findings suggest that GSP on OEC-M1 cells leads to cell cycle arrest by increasing the expression of p21(Cip1) /p27(Kip1) protein without functioning mitochondria-mediated apoptosis, whereas GSP on SCC-25 cells inhibits cell proliferation via both G1-phase arrest and mitochondria-mediated apoptosis in a dose-dependent manner as a result of alterations of Bcl-2. GSP also inhibits the migration and invasion of both cells, which are associated with the suppression of matrix metalloproteinases (MMPs), MMP-2 and MMP-9. CONCLUSION: Antiproliferative effectiveness of GSP is closely associated with the p53 status of OSCC cells. GSP displays chemoadjuvant potential via cell cycle blockage and apoptotic induction. Our findings clearly suggest that GSP may play a role as a novel chemopreventive or therapeutic agent for OSCC.
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Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Extrato de Sementes de Uva/farmacologia , Neoplasias Bucais/patologia , Preparações de Plantas/farmacologia , Proantocianidinas/farmacologia , Proteína Supressora de Tumor p53/efeitos dos fármacos , Vitis , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fase G1/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Invasividade Neoplásica , Proteínas Oncogênicas/efeitos dos fármacos , Mutação Puntual/genética , Inibidores de Proteínas Quinases/análise , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteína Supressora de Tumor p53/genéticaRESUMO
The association between air pollution and infant mortality has been inconsistently reported. A few studies have estimated short-term effects of air pollution on infants' health. This population-based case-control study aimed to examine the potential effects of air pollution on sudden infant death syndrome (SIDS) in the post-neonatal period in Taiwan during 1997-2002. Each case of infant death was matched with 20 randomly selected sex-matched controls who were born on the same day and were still alive. We obtained 24-h measurements of air pollutants and meteorological factors in each case and control with 1- to 14-day lags from 55 air-quality monitoring stations. After controlling for potential confounders, conditional logistic regression analysis was performed to estimate effects of air pollutants on SIDS (n = 398) and respiratory death (n = 121) among neonates. In single- and multi-pollutant models, we found that 100-ppb increment in carbon monoxide (Odds Ratio = 1.04-1.07) and 10-ppb increment in nitrogen dioxide (Odds Ratio = 1.20-1.35) with 1- to 14-day lags were associated with significant increase in SIDS, although a significant relationship between air pollution and respiratory death was not determined in 1- to 14-day lags. Short-term carbon monoxide and nitrogen dioxide exposure were associated with significant increase in SIDS in the post-neonatal period, with latency estimated within days before death.
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Poluentes Atmosféricos , Poluição do Ar , Morte Súbita do Lactente , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Estudos de Casos e Controles , Humanos , Lactente , Recém-Nascido , Dióxido de Nitrogênio/toxicidade , Material Particulado/análise , Material Particulado/toxicidade , Morte Súbita do Lactente/epidemiologia , Morte Súbita do Lactente/etiologia , Taiwan/epidemiologiaRESUMO
BACKGROUND: Exposure to air pollution has been associated with a wide range of adverse health effects; however, few studies addressed the relationship between ambient particulate matter as well as the compositions in particulate matter such as lead and the risk of small for gestational age (SGA) in offspring. The aim of this study is to investigate the effect of maternal exposure to criteria air pollutants and the lead in total suspended particulate matter during pregnancy on SGA births in Taiwan. METHODS: This population study consisted of 322,513 singleton live births in Taiwan between 1996 and 2002. Daytime (7 AM-7 PM) exposure to particulate matter ≤10 µm (PM10), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3), and monthly exposure to lead in total suspended particles (TSP) during each trimester were estimated. Generalized additive model (GAM) was used to assess the association between maternal exposure to particulate air pollutants and SGA births, taking into account potential confounders and gaseous air pollutants. RESULTS: We found significant association between the highest quartile (≥75th) of maternal PM10 exposure and SGA and demonstrated a significant exposure-response relationship. Furthermore, the highest quartile (≥75th) of maternal lead exposure was also associated with SGA during the second and third trimester of pregnancy, and there was a significant exposure-response relationship between maternal lead exposure and SGA during pregnancy. CONCLUSION: Maternal exposure to PM10 and lead in total suspended particulate matter during pregnancy was associated with an increased risk of SGA in offspring.
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Poluição do Ar/efeitos adversos , Recém-Nascido Pequeno para a Idade Gestacional , Exposição Materna/efeitos adversos , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Chumbo/efeitos adversos , Material Particulado/efeitos adversos , Gravidez , RiscoRESUMO
Although many studies have shown the association between smoking and the increased incidence and adverse prognosis of head and neck squamous cell carcinoma (HNSCC), the mechanisms and pharmaceutical targets involved remain unclear. Here, we integrated gene expression signatures, genetic alterations, and survival analyses to identify prognostic indicators and therapeutic targets for smoking HNSCC patients, and we discovered that the FDA-approved drug varenicline inhibits the target for cancer cell migration/invasion. We first identified 18 smoking-related and prognostic genes for HNSCC by using RNA-Seq and clinical follow-up data. One of these genes, CHRNB4 (neuronal acetylcholine receptor subunit beta-4), increased the risk of death by approximately threefold in CHRNB4-high expression smokers compared to CHRNB4-low expression smokers (log rank, p = 0.00042; hazard ratio, 2.82; 95% CI, 1.55-5.14), former smokers, and non-smokers. Furthermore, we examined the functional enrichment of co-regulated genes of CHRNB4 and its 246 frequently occurring copy number alterations (CNAs). We found that these genes were involved in promoting angiogenesis, resisting cell death, and sustaining proliferation, and contributed to much worse outcomes for CHRNB4-high patients. Finally, we performed CHRNB4 gene editing and drug inhibition assays, and the results validate these observations. In summary, our study suggests that CHRNB4 is a prognostic indicator for smoking HNSCC patients and provides a potential new therapeutic drug to prevent recurrence or distant metastasis.
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BACKGROUND: The relationship between the use of benzodiazepine-receptor agonists (BZRAs) and the risk of hospitalization for pneumonia remains inconclusive. This study aimed to explore the association between BZRA use and hospitalization for pneumonia in a general population. METHODS: This population-based nested case-control study used Taiwan's National Health Insurance Research Database between 2002 and 2012. We included only new users who did not have any BZRA prescriptions on record in the preceding 2 years and identified 12,002 subjects who were hospitalized for pneumonia (International Classification of Diseases, Ninth Revision codes 480-486, and 507) and 12,002 disease risk score-matched control subjects. A logistic regression model was used to determine the association of BZRA use and hospitalization for pneumonia. The exposure date, dose-response relationship, and class of BZRAs were comprehensively assessed. RESULTS: Current BZRA exposure was associated with hospitalization for pneumonia (adjusted OR [aOR],1.86; 95% CI,â1.75-1.97). Benzodiazepine hypnotic agents (aOR, 2.42; 95% CI, 2.16-2.71) had a higher risk of pneumonia than did benzodiazepine anxiolytic agents (aOR, 1.53; 95% CI, 1.44-1.63) or nonbenzodiazepine hypnotic agents (aOR, 1.60; 95% CI, 1.46-1.76). The pneumonia risk was increased with ultrashort-acting and short- to intermediate-acting agents, a higher defined daily dose, and the number of BZRAs used. Among individual BZRAs examined, midazolam had a higher risk (aOR, 5.77; 95% CI, 4.31-7.73) of hospitalization for pneumonia than did the others. CONCLUSIONS: This study suggests that there is a dose-response relationship between current BZRA use and the risk of hospitalization for pneumonia. In addition, benzodiazepine hypnotic agents, especially midazolam, present a greater risk of hospitalization for pneumonia. These findings reinforce the importance of a careful analysis of the benefits vs the risks of BZRA use.
Assuntos
Agonistas de Receptores de GABA-A/efeitos adversos , Pneumonia/induzido quimicamente , Adulto , Idoso , Ansiolíticos/efeitos adversos , Estudos de Casos e Controles , Clonazepam/efeitos adversos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Sistema de Registros , Fatores de Risco , Taiwan/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: To determine whether there is a bidirectional association between sleep apnea and diabetes mellitus. METHODS: We conducted longitudinal analyses of a population-based cohort over 12 years using Taiwan's national universal health insurance database. In analysis I, we included 102 355 individuals without type 2 diabetes mellitus at baseline and estimated the hazard ratio of incident diagnosis of type 2 diabetes mellitus for patients with and those without sleep apnea. In analysis II, we included 258 053 participants without sleep apnea at baseline and calculated the hazard ratio of developing sleep apnea for patients with and those without type 2 diabetes. RESULTS: In analysis I, the incidence rates of type 2 diabetes were 17.7 and 11.1 per 1000 person-years for patients with and those without sleep apnea, respectively. Patients with sleep apnea had an increased risk for diabetes (adjusted hazard ratio [aHR] = 1.33; 95% confidence interval [CI], 1.22 to 1.46). In analysis II, the risk for sleep apnea with diabetes was not statistically significant (aHR = 1.06; 95% CI, 0.98 to 1.16). These associations in both analyses did not substantively change after accounting for various latent periods. CONCLUSIONS: Baseline sleep apnea is associated with incident type 2 diabetes; however, the presence of type 2 diabetes cannot predict the development of sleep apnea.
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Diabetes Mellitus Tipo 2/complicações , Síndromes da Apneia do Sono/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Diabetes mellitus (DM) is a global pandemic metabolic disorder. In recent years, the amount of medical resources required for the treatment of diabetes has increased as diabetes rates have gradually risen. The combined effects of individual and neighbourhood socio-economic status (SES) on DM survival rates are still not clear, especially in patients of working age. In this paper, we aim to analyze the combined effects of neighbourhood and individual SES on DM survival rates in patients of working age in Taiwan. METHODS: The study of 23,781 people who were diagnosed with DM by using population-based study between 2002 and 2006. Each sample was followed up for 4 years or as a sensor case. We defined Individual SES and neighbourhood SES by each patient's job category and household income which characterized as advantaged or disadvantaged. Then we compared the survival rates by SES group used Cox proportional hazards model for adjust risk factors. RESULTS: The 4-year overall survival rates of diabetic patients were worst for those with low individual SES who living in advantaged neighbourhoods. After adjustment for patient characteristics, DM patients with high individual SES living in disadvantaged neighbourhoods had the same risk of mortality as those patients with high individual SES living in advantaged neighbourhoods (hazard ratio: 1.11; 95% confidence interval [CI]: 0.81-1.51). The study found that DM patients with low individual SES who live in disadvantaged areas had a greater risk of mortality than those with high SES (odds ratio: 2.57; 95% CI: 2.04-3.24). There were significant differences in survival rates between patients with high individual SES and patients with low individual SES. In contrast, the results did not statistically significant differences in survival rates between advantaged and disadvantaged neighbourhood SES groups. CONCLUSION: DM patients with low individual SES had the worst survival rate, regardless of whether they were living in a high or low SES neighbourhood area. The competitive cause of death, i.e., the fact that complications, rather than DM itself, are often the cause of death, may be the reason for the inverse relationship found between the effects of individual SES and neighbourhood SES on DM survival. We conclude that the socio-economic gradient in survival among DM patients may be the result of differences in access to medical treatment and attributes related to individual SES.
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Diabetes Mellitus/mortalidade , Fatores Etários , Idoso , Diabetes Mellitus/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores Socioeconômicos , Taxa de Sobrevida , Taiwan/epidemiologiaRESUMO
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.
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Neoplasias da Mama/enzimologia , MicroRNAs/metabolismo , Nucleotidiltransferases/metabolismo , Evasão Tumoral , Imunidade Adaptativa , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Epigênese Genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Coativador 3 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/metabolismo , Nucleotidiltransferases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Hipóxia Tumoral , Microambiente TumoralRESUMO
Identification of transcriptional regulatory sites plays an important role in the investigation of gene regulation. For this propose, we designed and implemented a data warehouse to integrate multiple heterogeneous biological data sources with data types such as text-file, XML, image, MySQL database model, and Oracle database model. The utility of the biological data warehouse in predicting transcriptional regulatory sites of coregulated genes was explored using a synexpression group derived from a microarray study. Both of the binding sites of known transcription factors and predicted over-represented (OR) oligonucleotides were demonstrated for the gene group. The potential biological roles of both known nucleotides and one OR nucleotide were demonstrated using bioassays. Therefore, the results from the wet-lab experiments reinforce the power and utility of the data warehouse as an approach to the genome-wide search for important transcription regulatory elements that are the key to many complex biological systems.
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Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Armazenamento e Recuperação da Informação/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Elementos Reguladores de Transcrição/genética , Análise de Sequência de DNA/métodos , Fatores de Transcrição/genética , Algoritmos , Sítios de Ligação , Sistemas de Gerenciamento de Base de Dados , Reconhecimento Automatizado de Padrão/métodos , Ligação Proteica , Alinhamento de Sequência/métodos , Biologia de Sistemas/métodosRESUMO
A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.
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Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Nitrosaminas/farmacologia , Compostos Organoplatínicos/farmacologia , Proteína de Ligação a Fosfatidiletanolamina/antagonistas & inibidores , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinógenos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Oxaliplatina , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Nucleoprotein (NP) is the most abundant type of RNA-binding viral protein in influenza A virus-infected cells and is necessary for viral RNA transcription and replication. Recent studies demonstrated that influenza NP is a valid target for antiviral drug development. The surface of the groove, covered with numerous conserved residues between the head and body domains of influenza A NP, plays a crucial role in RNA binding. To explore the mechanism by which NP binds RNA, we performed a series of site-directed mutagenesis in the RNA-binding groove, followed by surface plasmon resonance (SPR), to characterize the interactions between RNA and NP. Furthermore, a role of Y148 in NP stability and NP-RNA binding was evaluated. The aromatic residue of Y148 was found to stack with a nucleotide base. By interrupting the stacking interaction between Y148 and an RNA base, we identified an influenza virus NP inhibitor, (E, E)-1,7-bis(4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione; this inhibitor reduced the NP's RNA-binding affinity and hindered viral replication. Our findings will be useful for the development of new drugs that disrupt the interaction between RNA and viral NP in the influenza virus.
Assuntos
Antivirais/farmacologia , Curcumina/análogos & derivados , Vírus da Influenza A/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Proteínas do Core Viral/genética , Células A549 , Antivirais/química , Curcumina/química , Curcumina/farmacologia , Humanos , Vírus da Influenza A/metabolismo , Mutagênese Sítio-Dirigida , Proteínas do Nucleocapsídeo , Estrutura Terciária de Proteína , RNA/metabolismo , Motivos de Ligação ao RNA , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Proteínas do Core Viral/efeitos dos fármacos , Proteínas do Core Viral/metabolismoRESUMO
UNLABELLED: Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival. SUMMARY: DRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK-Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.
Assuntos
Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP27/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: Recent studies suggest that long-term exposure of the carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) found in tobacco smoke is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The underlying nicotine-mediated mechanism remains unclear. METHODS: An analysis of SCC-25 and Fadu cells with or without NNK exposure focusing on the evaluation of migration and invasion abilities, the expression of epithelial-mesenchymal transition, drug-resistance-related genes, properties of cancer stem cells (CSCs), and anti-apoptosis was performed. RESULTS: Long-term NNK exposure enhances migration and invasion with morphological alterations in a dose-dependently manner. Furthermore, NNK exposure also upregulates Snail, promotes sphere-forming ability, and overexpresses aldehyde dehydrogenase 1 (ALDH1), Nanog, OCT4, ABCG2, and MDR1. CONCLUSION: The current study confirmed that long-term NNK exposure plays a role in HNSCC by increasing anti-apoptosis and therapeutic resistance via the Snail-RKIP signaling pathway. Our data also suggest that α7 nicotinic acetylcholine receptor (α7-nAChR) inhibition or targeting Snail may provide a feasible rationale for preventing the progression of HNSCC.
Assuntos
Carcinógenos/farmacologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Nitrosaminas/farmacologia , Fatores de Transcrição , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Família Aldeído Desidrogenase 1 , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Neoplasias Hipofaríngeas/patologia , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Retinal Desidrogenase/efeitos dos fármacos , Retinal Desidrogenase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail , Neoplasias da Língua/patologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidoresRESUMO
BACKGROUND: Metastasis occurs in a series of discrete steps involving invasion, angiogenesis, lymphovascular space permeation, and establishment of secondary tumors. Malignant pleural effusion (MPE), a type of tumor metastasis, is usually a poor prognostic sign for patients with pulmonary adenocarcinoma, although its underlying mechanism has received less attention than other types of metastases have. The objective of the current study was to confirm whether cancer stem cells (CSCs) in MPE contribute to the "metastatic cascade" through the epithelial - mesenchymal transition (EMT), anoikis, and adaptation in the microenvironment. METHODS: Pulmonary tissue and corresponding cell blocks of MPE samples from 20 patients with primary adenocarcinoma were analyzed by immunohistochemical staining with CSC-representative markers (CD133, Nanog, and OCT-4) and EMT-associated markers (E-cadherin and vimentin). Correlations between these variables and clinico-pathological parameters were analyzed. Primary cultures from eight cases of MPE were investigated to characterize the CSC properties, including marker expression, sphere formation, and differentiation. RESULTS: Expressions of CSC-representative markers for 20 cases of MPE cell blocks were quite diverse and variable ranging from 15% to 90%. Stronger expression of CSC-representative markers and alteration of EMT-associated markers were found at the invasive fronts and in MPEs compared with the expression in primary pulmonary tumor tissues. The expression of OCT-4 in MPEs significantly related to distant metastasis and stage, as well as inversely correlated with patient survival. Primary cultures confirmed the CSC properties in MPE. Five of eight cases of MPE yielded adequate cell clusters, which also showed variable expressions of CSC markers in addition to sphere formation and the ability for differentiation and metastasis. CONCLUSION: This pilot study offers a better understanding of the metastatic cascade. Establishing a model of MPE will provide further insight into the role of CSCs in metastasis and may explain the high therapeutic failure rates for patients with MPE.