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Conjugated polymers (CPs), which emit in the second near-infrared window (NIR-II, 1000-1700 nm), are used as biomaterials for NIR-II fluorescence imaging because of their adjustable photophysical properties and high optical stability. However, the fluorescence signal of conventional CPs is quenched in an aggregated state due to strong π-π stacking, which results in the closure of the radiation attenuation pathway. To solve this problem, the aggregation-induced emission effect is considered a reasonable strategy for enhancing the aggregative fluorescence of IR-II emitters. We herein report NIR-II conjugated polymers with typical AIE characteristics (αAIE > 3) by changing the side chain structure of receptor units and the conjugation degree of donors. Conjugated polymer nanoparticles (PoBVT NPs) exhibit outstanding performance in NIR-II fluorescence imaging (QY = 1.94%) and highly effective photothermal therapy (η = 45%). In vivo studies have shown that the location of tumors can be accurately obtained by NIR-II FL/NIR-II PA imaging, and there is a significant anti-tumor effect after laser irradiation. This work offers prospects for the design of multifunctional conjugated polymers for NIR-II FL/PA imaging to guide NIR-II PTT applications.
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Rayos Infrarrojos , Polímeros , Polímeros/química , Animales , Humanos , Ratones , Nanomedicina Teranóstica , Imagen Óptica , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Tamaño de la Partícula , Terapia Fototérmica , Estructura MolecularRESUMEN
Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Metionina , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Metionina/metabolismo , Ratones Desnudos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , OncogenesRESUMEN
Introduction: The prognosis of bladder cancer (BLCA) and response to immune checkpoint inhibitors (ICIs) are determined by multiple factors. Existed biomarkers for predicting the effect of immunotherapy cannot accurately predict the response of BLCA patients to ICIs. Methods: To further accurately stratify patients' response to ICIs and identify potential novel predictive biomarkers, we used the known T cell exhaustion (TEX)-related specific pathways, including tumor necrosis factor (TNF), interleukin (IL)-2, interferon (IFN)-g, and T- cell cytotoxicpathways, combined with weighted correlation network analysis (WGCNA) to analyze the characteristics of TEX in BLCA in detail, constructed a TEX model. Results: This model including 28 genes can robustly predict the survival of BLCA and immunotherapeutic efficacy. This model could divide BLCA into two groups, TEXhigh and TEXlow, with significantly different prognoses, clinical features, and reactivity to ICIs. The critical characteristic genes, such as potential biomarkers Charged Multivesicular Body Protein 4C (CHMP4C), SH2 Domain Containing 2A (SH2D2A), Prickle Planar Cell Polarity Protein 3 (PRICKLE3) and Zinc Finger Protein 165 (ZNF165) were verified in BLCA clinical samples by real-time quantitative chain reaction (qPCR) and immunohistochemistry (IHC). Discussion: Our findings show that the TEX model can serve as biological markers for predicting the response to ICIs, and the involving molecules in the TEX model might provide new potential targets for immunotherapy in BLCA.
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The effectiveness of phototheranostics induced immunotherapy is still hampered by limited light penetration depth, the complex immunosuppressive tumor microenvironment (TME) and the low efficiency of immunomodulator drug delivery. Herein, self-delivery and TME responsive NIR-II phototheranostic nanoadjuvants (NAs) were fabricated to suppress the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy (PTT-CDT) and immune remodeling. The NAs were constructed by the self-assembly of ultrasmall NIR-II semiconducting polymer dots and the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. Under acidic TME, the NAs responsively disintegrated and released therapeutic components, which enable NIR-II fluorescence/photoacoustic/magnetic resonance imaging-guided tumor PTT-CDT. Moreover, the synergistic treatment of PTT-CDT could induce significant tumor immunogenic cell death and evoke highly efficacious cancer immunosurveillance. The released R848 stimulated the maturation of dendritic cells, which both amplified the antitumor immune response by modulating and remodeling the TME. The NAs present a promising integration strategy of polymer dot-metal ion coordination and immune adjuvants for precise diagnosis and amplified anti-tumor immunotherapy against deep-seated tumors. STATEMENT OF SIGNIFICANCE: The efficiency of phototheranostics induced immunotherapy is still limited by insufficient light penetration depth, low immune response and the complex immunosuppressive tumor microenvironment (TME). In order to improve the efficacy of immunotherapy, self-delivery NIR-II phototheranostic nanoadjuvants (PMR NAs) were successfully fabricated via the facile coordination self-assembly of ultra-small NIR-II semiconducting polymer dots and toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. PMR NAs not only enable TME responsive cargo release and NIR-II fluorescence/photoacoustic/magnetic resonance imaging mediated precise localization of tumors, but also achieve synergistic photothermal-chemodynamic therapy, evoking an effective anti-tumor immune response by ICD effect. The responsively released R848 could further amplify the efficiency of immunotherapy by reversing and remodeling the immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor growth and lung metastasis.
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Nanopartículas , Neoplasias , Humanos , Fototerapia/métodos , Manganeso , Polímeros , Neoplasias/terapia , Metales , Inmunoterapia/métodos , Imagen Multimodal , Receptores Toll-Like , Nanopartículas/uso terapéutico , Microambiente Tumoral , Línea Celular TumoralRESUMEN
BACKGROUND: New therapeutic approaches are required to improve the outcomes of lung cancer (LC), a leading cause of cancer-related deaths worldwide. Chinese herbal medicine formulae widely used in China provide a unique opportunity for improving LC treatment, and the Shuang-Huang-Sheng-Bai (SHSB) formula is a typical example. However, the underlying mechanisms of action remains unclear. PURPOSE: This study aimed to confirm the efficacy of SHSB against lung adenocarcinoma (LUAD), which is a major histological type of LC, unveil the downstream targets of this formula, and assess the clinical relevance and biological roles of the newly identified target. METHODS: An experimental metastasis mouse model and a subcutaneous xenograft mouse model were used to evaluate the anti-cancer activity of SHSB. Multi-omics profiling of subcutaneous tumors and metabolomic profiling of sera were performed to identify downstream targets, especially the metabolic targets of SHSB. A clinical trial was conducted to verify the newly identified metabolic targets in patients. Next, the metabolites and enzymes engaged in the metabolic pathway targeted by SHSB were measured in clinical samples. Finally, routine molecular experiments were performed to decipher the biological functions of the metabolic pathways targeted by SHSB. RESULTS: Oral SHSB administration showed overt anti-LUAD efficacy as revealed by the extended overall survival of the metastasis model and impaired growth of implanted tumors in the subcutaneous xenograft model. Mechanistically, SHSB administration altered protein expression in the post-transcriptional layer and modified the metabolome of LUAD xenografts. Integrative analysis demonstrated that SHSB markedly inhibited acetyl-CoA synthesis in tumors by post-transcriptionally downregulating ATP-citrate lyase (ACLY). Consistently, our clinical trial showed that oral SHSB administration declined serum acetyl-CoA levels of patients with LC. Moreover, acetyl-CoA synthesis and ACLY expression were both augmented in clinical LUAD tissues of patients, and high intratumoral ACLY expression predicted a detrimental prognosis. Finally, we showed that ACLY-mediated acetyl-CoA synthesis is essential for LUAD cell growth by promoting G1/S transition and DNA replication. CONCLUSION: Limited downstream targets of SHSB for LC treatment have been reported in previous hypothesis-driven studies. In this study, we conducted a comprehensive multi-omics investigation and demonstrated that SHSB exerted its anti-LUAD efficacy by actively and post-transcriptionally modulating protein expression and particularly restraining ACLY-mediated acetyl-CoA synthesis.
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Adenocarcinoma del Pulmón , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Humanos , Ratones , Animales , ATP Citrato (pro-S)-Liasa/genética , ATP Citrato (pro-S)-Liasa/metabolismo , Acetilcoenzima A/metabolismo , Medicamentos Herbarios Chinos/farmacología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The phototheranostics in the second near-infrared window (NIR-II) have proven to be promising for the precise cancer theranostics. However, the non-responsive and "always on" imaging mode lacks the selectivity, leading to the poor diagnosis specificity. Herein, a tumor microenvironment (TME) activated NIR-II phototheranostic nanoplatform (Ag2 S-Fe(III)-DBZ Pdots, AFD NPs) is designed based on the principle of Förster resonance energy transfer (FRET). The AFD NPs are fabricated through self-assembly of Ag2 S QDs (NIR-II fluorescence probe) and ultra-small semiconductor polymer dots (DBZ Pdots, NIR-II fluorescence quencher) utilizing Fe(III) as coordination nodes. In normal tissues, the AFD NPs maintain in "off" state, due to the FRET between Ag2 S QDs and DBZ Pdots. However, the NIR-II fluorescence signal of AFD NPs can be rapidly "turn on" by the overexpressed GSH in tumor tissues, achieving a superior tumor-to-normal tissue (T/NT) signal ratio. Moreover, the released Pdots and reduced Fe(II) ions provide NIR-II photothermal therapy (PTT) and chemodynamic therapy (CDT), respectively. The GSH depletion and NIR-II PTT effect further aggravate CDT mediated oxidative damage toward tumors, achieving the synergistic anti-tumor therapeutic effect. The work provides a promising strategy for the development of TME activated NIR-II phototheranostic nanoprobes.
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Nanopartículas , Neoplasias , Humanos , Compuestos Férricos , Terapia Fototérmica , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Transferencia Resonante de Energía de Fluorescencia , Imagen Óptica , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Introduction: Dysbiosis of the lower airway flora is associated with lung cancer, of which the relationship between Streptococcus, especially pathogenic Streptococcus pneumoniae (S. pneumoniae), and the progression of lung cancer are unclear. Methods: Bronchoalveolar lavage fluid (BALF) samples were prospectively collected from patients with pulmonary nodules during diagnostic bronchoscopy, and finally included 70 patients diagnosed with primary lung cancer and 20 patients with benign pulmonary nodules as the disease control group. The differential flora was screened by 16S ribosomal RNA (rRNA) gene amplicon sequencing. An in vitro infection model of lung adenocarcinoma (LUAD) cells exposed to S.pneumoniae was established to observe its effects on cell migration and invasion ability. Exploring the molecular mechanisms downstream of DDIT4 through its loss- and gain-of-function experiments. Results: 16S rRNA sequencing analysis showed that the abundance of Streptococcus in the lower airway flora of lung cancer patients was significantly increased. After exposure to S. pneumoniae, A549 and H1299 cells significantly enhanced their cell migration and invasion ability. The results of DDIT4 loss- and gain-of-function experiments in A549 cells suggest that up-regulation of DDIT4 activates the mTORC2/Akt signaling pathway, thereby enhancing the migration and invasion of A549 cells while not affecting mTORC1. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) showed that S. pneumoniae was enriched in LUAD tissues, and DDIT4 expression was significantly higher in cancer tissues than in non-cancerous tissues. The increased expression of DDIT4 was also related to the poor prognosis of patients with LUAD. Discussion: The data provided by this study show that S. pneumoniae enriched in the lower airway of patients with lung cancer can up-regulate DDIT4 expression and subsequently activate the mTORC2/AKT signal pathway, thereby increasing the migration and invasion abilities of A549 cells. Our study provides a potential new mechanism for targeted therapy of LUAD.
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OBJECTIVES: To recognise clinical features of COVID-19 pneumonia and its differences from influenza pneumonia. METHODS: 246 patients were enrolled into COVID-19 cohort and 120 patients into influenza cohort. All data were collected and analysed retrospectively. The variables under focus included demographic, epidemiological, clinical, laboratory and imaging characteristics of COVID-19 pneumonia and comparison were made with influenza pneumonia. RESULTS: The COVID-19 cohort included 53.25% female and 46.75% male. Their main symptom was fever; while 28.05% of patients had only initially fever; 21.54% of them remained feverless. After excluding prior kidney diseases, some patients showed abnormal urinalysis (32.11%), elevated blood creatinine (15.04%) and blood urea nitrogen (19.11%). Typical CT features included ground glass opacity, consolidation and band opacity, which could present as characteristic 'bat wing sign'. Our data showed that male, aged 65 or above, smoking, with comorbidities including diabetes, cardiovascular and kidney diseases, would experience more severe COVID-19 pneumonia. In comparison, COVID-19 cohort showed significantly higher incidence of clustering; the influenza cohort showed higher rate of fever. Both cohorts showed reduced lymphocyte numbers; however, 6 influenza patients showed lymphocytes increased, which was statistical significant compared with COVID-19 cohort. Also, influenza cohort displayed higher white blood cell counts and PCT values. CONCLUSION: There is no significant gender difference in the incidence of COVID-19 pneumonia. It predominantly affects the lung as well as the kidney. Age, smoking and comorbidities could contribute to disease severity. Although COVID-19 is more infectious, the rate of secondary bacterial infection is lower than influenza.
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Betacoronavirus , Infecciones por Coronavirus/diagnóstico , Gripe Humana/diagnóstico , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Adolescente , Adulto , Anciano , COVID-19 , Infecciones por Coronavirus/complicaciones , Diagnóstico Diferencial , Femenino , Humanos , Gripe Humana/complicaciones , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Estudios Retrospectivos , SARS-CoV-2 , Evaluación de Síntomas , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Vanadium phosphate (VPO4) is attracting extensive attention because of its advantages of low cost, stable structure and high theoretical capacity. However, similar to other phosphates, VPO4 suffers from low electrical conductivity and large volume expansion, adversely influencing its electrochemical performance and thus limiting its application as an anode in lithium and sodium ion batteries. Herein, we propose a novel, facile strategy based on the organic-inorganic network of a nanostructured hybrid hydrogel for immobilizing VPO4 in a hierarchically porous carbon framework (3DHP-VPO4@C). VPO4 chemically interacts with the carbon framework via a P-C bond, functioning as a buffer layer to maintain structural stability during charge/discharge cycles. The carbon framework offers an efficient pathway for electron and Li+/Na+ transport to ensure high electronic conductivity of the electrode. The 3DHP-VPO4@C anode exhibits excellent lithium and sodium storage performances, and notably high capacities of 957 mA h g-1 at 0.1 A g-1 and 345.3 mA h g-1 at 5 A g-1 for lithium ion batteries. Full cells consisting of a LiFePO4 cathode and the 3DHP-VPO4@C anode also prove to have superior cycling stability and rate performance for LIBs.
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The occurrence and development of hepatocellular carcinoma (HCC) is a complicate process involved in genetic mutation and epigenetic regulation. Successful HCC therapy needs multi-targets be involved. The aim of this study was to provide a triple effective RNA (teRNA) which composed of the specific siRNAs targeting NET-1 and VEGF and dsRNA activating TLR3, and explored its anti-HCC roles and mechanism. Real-time quantitative PCR (RT-qPCR), Western blot, immunofluorescence staining, MTT, Annexin V-FITC flow cytometry, Transwell and in-vitro Angiogenesis assay were used to measure the cell biological functions and protein expression analysis. Furthermore in in-vivo mouse model, teRNA inhibited tumor growth were detected by immunohistochemistry and TUNEL assay. Results showed that the proliferation, migration and angiogenesis of HCC cells were inhibited by teRNA effectively, the cell apoptosis also was induced, and further tumor growth was suppressed in-vivo. The gene silencing mechanism of teRNA was in an Ago2-dependent manner with no interferon response. The study suggests that NET-1, VEGF and TLR3 might be better targets for HCC treatment and combined these targets in form of a multi-target small RNA, teRNA could be a stagey for the development of anti-HCC drugs.
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Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments.
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BACKGROUND: It is reported that the iron-responsive element-binding protein 2 (IREB2) gene rs2568494 polymorphism might be associated with COPD risk. The purpose of this meta-analysis was to collect all eligible studies to review the association between IREB2 gene rs2568494 polymorphism and susceptibility to COPD. MATERIAL/METHODS: We carried out a comprehensive document search of electronic databases of PubMed, MEDLIN, Web of Science, and included 4 eligible studies that examined the association between IREB2 rs2568494 polymorphism and COPD susceptibility. We performed a meta-analysis of these studies based on IREB2 rs2568494 genotypes. RESULTS: After meta-analysis with fixed or random effects, no significant associations were found under the heterozygote model (GG/GA; OR=0.908, 95%CI: 0.790-1.043; P=0.172), homozygote model (GG/AA; OR=0.880, 95%CI: 0.497-1.557; P=0.661), dominant model (GG/AA+GA; OR=0.941, 95%CI: 0.748-1.182; P=0.599), or allelic model (G/A; OR=0.953, 95%CI: 0.770-1.179; P=0.655). However, we found a significant correlation under the recessive model (AA/GA+GG; OR=1.384, 95%CI: 1.092-1.755; P=0.007). CONCLUSIONS: The current results revealed that there was significant association between IREB2 gene rs2568494 polymorphism with susceptibility to COPD; the presence of allelic A might a genetic factor conferring susceptibility to COPD.
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Predisposición Genética a la Enfermedad , Proteína 2 Reguladora de Hierro/genética , Polimorfismo de Nucleótido Simple/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Anciano , Alelos , Estudios de Casos y Controles , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sesgo de Publicación , Factores de RiesgoRESUMEN
Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an Eµ-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Carcinogénesis/genética , Péptido Hidrolasas/fisiología , Proteínas Proto-Oncogénicas c-myc/fisiología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Animales , Complejo del Señalosoma COP9 , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Linfoma/metabolismo , Linfoma/fisiopatología , Ratones , Ratones Transgénicos/genética , Neoplasias Experimentales/genética , Péptido Hidrolasas/biosíntesis , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Ligasas SKP Cullina F-box/fisiología , Transcripción Genética/fisiología , UbiquitinaciónRESUMEN
HER2/neu oncogene is frequently overexpressed in various types of cancer, and the (PI3K)-Akt signaling pathway is often activated in HER2-overexpressing cancer cells. CSN6, subunit 6 of the COP9 signalosome complex, is pivotal in regulating MDM2 to destabilize p53, but its upstream regulators remain unclear. Here we show that the HER2-Akt axis is linked to CSN6 regulation, and that Akt is a positive regulator of CSN6. Ectopic expression of Akt can increase the expression of CSN6; accordingly, Akt inhibition leads to CSN6 destabilization. Mechanistic studies show that Akt causes CSN6 phosphorylation at Ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of CSN6. Significantly, Akt's positive impact on CSN6 elevation translates into p53 degradation, potentiating transformational activity and increasing DNA damage. Akt inhibition can attenuate these defects caused by CSN6. These data suggest that Akt is an important positive regulator of CSN6, and that activation of Akt in many types of cancer could lead to abnormal elevation of CSN6 and result in downregulated p53 and increased DNA damage, which promotes cancer cell growth.
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Complejos Multiproteicos/metabolismo , Péptido Hidrolasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Secuencia de Aminoácidos , Aurora Quinasas , Complejo del Señalosoma COP9 , Línea Celular Tumoral , Daño del ADN , Células HCT116 , Células HEK293 , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Estabilidad Proteica , Subunidades de Proteína/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , Ubiquitina/metabolismo , UbiquitinaciónRESUMEN
AZ64 is a novel antitumor agent designed as a tropomyosin-related kinase (Trk) inhibitor; however, its effect on lung cancer and its mechanism of action remain unclear. This study aimed to elucidate the antitumor activity of AZ64 and its mechanism of action against non-small cell lung cancer (NSCLC). Our results demonstrate that AZ64 has a potent anti-proliferative effect on NSCLC cells and acts in a dose- and time-dependent manner. We also demonstrate that AZ64 suppresses the anchorage-independent growth and invasion of NSCLC cells. In vivo experiments demonstrated that AZ64 significantly reduced the tumor growth of NSCLC xenografts in nude mice and was well-tolerated. Mechanistic experiments revealed that AZ64 induced the G2/M arrest of NSCLC cells by the accumulation of phospho-cdc2 (Tyr15) at the G2/M transition, following the downregulation of Cdc25C expression. Collectively, our data demonstrate that AZ64 is a potential antitumor drug that may be used for the treatment of NSCLC, which functions by targeting the G2/M transition via the inhibition of the dephosphorylation of phospho-cdc2 (Tyr15).
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos/efectos de los fármacos , Cromosomas Humanos/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Microtúbulos/metabolismo , Proteínas Quinasas/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immune inhibitory receptors play an important role in organ transplantation, autoimmune diseases and cancers. Immunoglobulin-like transcript (ILT)2 and ILT3 belong to the inhibitory receptors of the ILT family, which have been reported to regulate a broad range of cellular functions involved in the immune response. They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are related to immune regulation. Although ILT receptors have been studied in dendritic cells (DCs), T cells, NK cells and other cell types, the expression and clinical significance of ILT2 and ILT3 in gastric cancer have yet to be elucidated. Here, the expression of ILT2 and ILT3 in gastric cancer cell lines and pathologic tissues, as well as their effects on the cytotoxicity of NK92MI against the gastric cancer cell lines MKNI with ILT2lowILT3low and HGC-27 with ILT2highILT3high were detected. The results suggest that ILT2 and ILT3 are expressed with diverse degrees in gastric cancer cells and tissues, and the expression of ILT2 is related with differentiation and size of tumors. Furthermore, the cytotoxic activity of NK92MI against the MKNI cell line was stronger than that against HGC-27. This study indicates that ILT2 and ILT3 play a key role in gastric cancer immune escape, and ILT2 may be a new target in the clinical diagnosis and treatment of gastric cancer.
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Antígenos CD/metabolismo , Regulación Neoplásica de la Expresión Génica , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Antígenos CD/genética , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Humanos , Inmunohistoquímica , Receptor Leucocitario Tipo Inmunoglobulina B1 , Masculino , Glicoproteínas de Membrana , Persona de Mediana Edad , Receptores de Superficie Celular/genética , Receptores Inmunológicos/genética , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Epigenetic silencing is a common mechanism to inactivate tumor suppressor genes during carcinogenesis. Enhancer of Zeste 2 (EZH2) is the histone methyltransferase subunit in polycomb repressive complex 2 which mediates transcriptional repression through histone methylation. EZH2 overexpression has been linked to aggressive phenotypes of certain cancers. However, the mechanism that EZH2 played in promoting malignancy in non-small cell lung cancer (NSCLC) remains unclear. In addition, the correlation of EZH2 overexpression and the prognosis of NSCLC patients in non-Asian cohort need to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Up-regulation of EZH2 was found in NSCLC cells compared with normal human bronchial epithelial cells by western blot assay. Upon EZH2 knockdown using small interfering RNA (siRNA), the proliferation, anchorage-independent growth and invasion of NSCLC cells were remarkably suppressed with profound induction of G1 arrest. Furthermore, the expression of cyclin D1 was notably reduced whereas p15(INK4B), p21(Waf1/Cip1) and p27(Kip1) were increased in NSCLC cells after EZH2-siRNA delivery. To determine whether EZH2 expression contributes to disease progression in patients with NSCLC, Taqman quantitative real-time RT-PCR was used to measure the expression of EZH2 in paired tumor and normal samples. Univariate analysis revealed that patients with NSCLC whose tumors had a higher EZH2 expression had significantly inferior overall, disease-specific, and disease-free survivals compared to those whose tumors expressed lower EZH2 (P = 0.005, P = 0.001 and P = 0.003, respectively). In multivariate analysis, EZH2 expression was an independent predictor of disease-free survival (hazard ratio = 0.450, 95% CI: 0.270 to 0.750, P = 0.002). CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that EZH2 overexpression is critical for NSCLC progression. EZH2 mRNA levels may serve as a prognostic predictor for patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Ciclo Celular/genética , Neoplasias Pulmonares/genética , Complejo Represivo Polycomb 2/genética , ARN Mensajero/genética , Bronquios/metabolismo , Bronquios/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Complejo Represivo Polycomb 2/metabolismo , Pronóstico , ARN Mensajero/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The presence of glutathione S-transferase (GST) pi1 (GSTP1) or multidrug resistance gene 1 (MDR1) promoter methylation in lung cancer was studied for the first time to the authors' knowledge; and, to date, the clinical significance of methylation is not clear. The objective of the current study was to determine the promoter methylation status of GSTP1 and MDR1, which encode GST-pi and P-glycoprotein (Pgp), respectively, in patients with bronchioloalveolar carcinoma (BAC) and to investigate whether methyltransferase 1 (DNMT1)-mediated GSTP1 or MDR1 methylation are responsible for disease progression and prognosis in patients with BAC. METHODS: Protein expression levels of DNTM1, GST-pi, and Pgp were determined by immunohistochemistry in samples from 36 patients with BAC. Promoter methylation status of the GSTP1 and MDR1 genes was determined by using methylation-specific polymerase chain reaction analysis. RESULTS: The results demonstrated a significant correlation between the methylation of the GSTP1 or MDR1 promoters and negative expression of their respective proteins in BAC (P < .05). A significant correlation also was demonstrated between GSTP1 methylation and recurrence-free and overall survival of patients with BAC. DNMT1 protein expression levels were correlated with GSTP1 promoter methylation and patient prognosis (P < .05). However, no correlation was observed between DNMT1 expression and MDR1 methylation. CONCLUSIONS: GSTP1 promoter methylation mediated by DNMT1 may promote BAC progression and could serve as a poor prognostic indicator for patients with this disease. DNMT1 protein expression also may be considered as a prognostic indicator. Methylation of the MDR1 promoter may be mediated through pathways other than DNMT1 in BAC and does not appear to be associated with disease progression or patient prognosis.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adenocarcinoma Bronquioloalveolar/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Gutatión-S-Transferasa pi/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Regiones Promotoras Genéticas , Adulto , Anciano , ADN (Citosina-5-)-Metiltransferasa 1 , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND & OBJECTIVE: Survivin, an anti-apoptosis gene, expresses in most tumors, and takes part in tumor angiogenesis. This study was to investigate microvessel density (MVD) and expressions of Survivin and vascular endothelial growth factor (VEGF) in non-small cell lung cancer (NSCLC), and explore their correlations to clinicopathologic features of NSCLC. METHODS: MVD and expressions of Survivin and VEGF in 96 specimens of NSCLC tissues, 31 specimens of tumor adjacent tissues, and 20 specimens of benign lesions were detected by SP immunohistochemistry; their interrelations and correlations to clinicopathologic features of NSCLC were analyzed. RESULTS: Positive rate of Survivin was significantly higher in NSCLC than in adjacent tissues and benign lesions (69.8% vs. 16.1% and 0, P<0.05); its expression was related with differentiation and TNM stage of NSCLC. Positive rate of VEGF was significantly higher in NSCLC than in adjacent tissues and benign lesions (72.9% vs. 45.2% and 25.0%, P<0.05); its expression was related with lymph node metastasis and TNM stage of NSCLC. MVD was significantly higher in NSCLC than in adjacent tissues and benign lesions (24.44+/-7.79 vs. 19.37+/-5.26 and 11.83+/-6.25, P<0.05), and was related with lymph node metastasis and TNM stage of NSCLC. Survivin expression was positively correlated with VEGF expression and MVD. CONCLUSION: Survivin is overexpressed in NSCLC, which relates with differentiation and TNM stage of NSCLC and takes part in angiogenesis.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Masculino , Microcirculación/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Survivin , Tuberculoma/metabolismo , Tuberculoma/patología , Tuberculosis Pulmonar/metabolismo , Tuberculosis Pulmonar/patologíaRESUMEN
OBJECTIVE: To observe the changes of serum interleukin (IL)-12, IL-13 and lung function in asthmatic patients and to evaluate the influence of glucocorticoid on them. METHODS: The serum samples were obtained from (1) 25 asthmatic patients with acute asthma attack before and after one week course of oral prednisone, (2) 20 asthmatic patients in remission stage, and (3) 15 healthy volunteers. Serum IL-12 and IL-13 were determined with sandwich ELISA. Lung ventilatory function forced expiratory volume in one second (FEV(1)) and respiratory impedance airway resistance (R(5)) were measured in all patients. RESULTS: (1) Serum level of IL-12 in asthma attack group was significantly lower than that in asthma remission group (P < 0.05); both were significantly lower than that in normal control group (P < 0.01); in asthma attack group IL-12 level after prednisone treatment was significantly higher than that before treatment (P < 0.01). (2) Serum level of IL-13 in asthma attack group was significantly higher than that in asthma remission group (P < 0.01); both were significantly higher than that in normal control group (P < 0.01); in asthma attack group IL-13 level after prednisone treatment was significantly lower than that before treatment (P < 0.01). Correlation analysis showed that the serum level of IL-12 was positively correlated to FEV(1) and negatively correlated to R(5) and to serum level of IL-13 (r(1) = 0.458, r(2) = -0.516, and r(3) = -0.549, respectively; P < 0.05 and P < 0.01); the serum level of IL-13 was negatively correlated to FEV(1) and positively correlated to R(5) (r(1) = -0.493, and r(2) = 0.528, respectively; P < 0.05). CONCLUSION: The secretion of IL-12 and IL-13 was impaired in asthma with a significant increase in serum level of IL-13 and decrease in serum level of IL-12. Glucocorticoid could downregulate the serum level of IL-13 and upregulate the serum level of IL-12, redress the imbalance of IL-12/IL-13, and improve lung function in asthmatic patients.