RESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases. The RNA binding protein, QKI, belongs to the STAR family and plays tumor-suppressive functions in NSCLC. QKI-5 is a major isoform of QKIs and is predominantly expressed in NSCLC. However, the underlying mechanisms of QKI-5 in NSCLC progression remain unclear. We found that QKI-5 regulated microRNA (miRNA), miR-196b-5p, and its expression was significantly up-regulated in NSCLC tissues. Up-regulated miR-196b-5p promotes lung cancer cell migration, proliferation, and cell cycle through directly targeting the tumor suppressors, GATA6 and TSPAN12. Both GATA6 and TSPAN12 expressions were down-regulated in NSCLC patient tissue samples and were negatively correlated with miR-196b-5p expression. Mouse xenograft models demonstrated that miR-196b-5p functions as a potent onco-miRNA, whereas TSPAN12 functions as a tumor suppressor in NSCLC in vivo. QKI-5 bound to miR-196b-5p and influenced its stability, resulting in up-regulated miR-196b-5p expression in NSCLC. Further analysis showed that hypomethylation in the promoter region enhanced miR-196b-5p expression in NSCLC. Our findings indicate that QKI-5 may exhibit novel anticancer mechanisms by regulating miRNA in NSCLC, and targeting the QKI5â¼miR-196b-5pâ¼GATA6/TSPAN12 pathway may enable effectively treating some NSCLCs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Factor de Transcripción GATA6/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Tetraspaninas/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Factor de Transcripción GATA6/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Ratones , Ratones Desnudos , MicroARNs/genética , Tetraspaninas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with a low cure rate. Periplaneta americana is a traditional American Cockroach and reportedly has potential therapeutic roles for UC treatment; however, its mechanisms remain unclear. To address this, we investigated the therapeutic effects and underlying molecular mechanisms of Ento-A, a Periplaneta americana extract, in a dextran sulfate sodium (DSS)-induced chronic and recurrent UC mouse model. Ento-A treatment decreased pro-inflammatory cytokine secretion, disease activity index (DAI), colon mucosa damage index (CMDI), histopathological scores (HS), and increased colon length. Additionally, Ento-A effectively increased interleukin-4 (IL-4), and forkhead transcription factor protein 3 (Foxp3) expression levels, while it abated interferon-γ (IFN-γ) and IL-17 levels in spleen lymphocytes. Conversely, in mesenteric lymph nodes, IL-4 and Foxp3 expression were decreased, while IFN-γ and IL-17 expression was increased. Furthermore, Ento-A blocked p-PI3K, p-AKT,*and p-NF-κB activation. In conclusion, Ento-A improved UC symptoms and exerted therapeutic effects by regulating immune responses and inhibiting PI3K/AKT/NF-κB signaling.
Asunto(s)
Colitis Ulcerosa , Colitis , Periplaneta , Animales , Colitis/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colon , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Inmunidad , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Ratones , FN-kappa B/metabolismo , Periplaneta/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome and currently no effective targeted therapies are available. Alantolactone (ATL), a sesquiterpene lactone, has been shown to have potential anti-tumour activity against various cancer cells. However, the underlying mechanism and therapeutic effect of ATL in the TNBC are largely unknown. In the present study, we found that ATL suppresses TNBC cell viability by reactive oxygen species (ROS) accumulation and subsequent ROS-dependent endoplasmic reticulum (ER) stress both in vitro and in vivo. Thioredoxin reductase 1 (TrxR1) expression and activity of were significantly up-regulated in the TNBC tissue specimens compare to the normal adjacent tissues. Further analyses showed that ATL inhibits the activity of TrxR1 both in vitro and in vivo in TNBC and knockdown of TrxR1 in TNBC cells sensitized ATL-induced cell apoptosis and ROS increase. These results will provide pre-clinical evidences that ATL could be a potential therapeutic agent against TNBC by promoting ROS-ER stress-mediated apoptosis through partly targeting TrxR1.
Asunto(s)
Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Lactonas/farmacología , Sesquiterpenos de Eudesmano/farmacología , Tiorredoxina Reductasa 1/genética , Reductasa de Tiorredoxina-Disulfuro/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Estrés del Retículo Endoplásmico/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Especies Reactivas de Oxígeno/metabolismo , Tiorredoxina Reductasa 1/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Lung cancer is a leading cause of cancer-related death worldwide. Cyanopyridines and aminocyanopyridines with carbon-nitrogen bonds have been proved to exert significant anticancer, antibacterial, and anti-inflammatory effects. In this study, we showed that aminocyanopyridine 3o and 3k displaying potent antitumor activity via inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway. They blocked the constitutive STAT3 phosphorylation in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptosis factors. Most importantly, 3o also inhibited interleukin-6-induced STAT3 activation and nuclear localization. Furthermore, 3o significantly inhibited the tumor growth of H460-derived xenografts. Taken together, these findings suggest that 3o and 3k are promising therapeutic drug candidates for lung cancer by inhibiting persistent STAT3 signaling.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Piridinas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Células A549 , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Interleucina-6/metabolismo , Janus Quinasa 2/biosíntesis , Janus Quinasa 3/biosíntesis , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.
Asunto(s)
Antagomirs/farmacología , Neoplasias Encefálicas/terapia , Regulación Neoplásica de la Expresión Génica , Glioblastoma/terapia , MicroARNs/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Animales , Antagomirs/química , Antagomirs/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Portadores de Fármacos , Femenino , Receptores de Folato Anclados a GPI/genética , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Nanopartículas/química , Oligonucleótidos/química , Oligonucleótidos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Regiones no Traducidas 3'/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Islas de CpG/genética , Metilación de ADN/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Sistema de Señalización de MAP Quinasas/genética , Ratones Desnudos , MicroARNs/genética , Invasividad Neoplásica , Fenotipo , Regiones Promotoras Genéticas/genética , Proteínas/genética , Proteína Smad4/genética , Regulación hacia Arriba/genéticaRESUMEN
TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias Pulmonares/patología , MicroARNs/fisiología , FN-kappa B/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Transcripción GenéticaRESUMEN
Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.
Asunto(s)
Pueblo Asiatico/genética , Cromosomas Humanos Par 15 , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/genética , Alelos , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Japón , Masculino , Oportunidad Relativa , Reproducibilidad de los Resultados , FumarRESUMEN
Metastasis is the principal cause of cancer death and occurs through multiple, complex processes that involve the concerted action of many genes. A number of studies have indicated that the Fragile Histidine Triad (FHIT) gene product, FHIT, functions as a tumor suppressor in a variety of common human cancers. Although there are suggestions of a role for FHIT loss in progression of various cancers, a role for such loss in metastasis has not been defined. Here, via in vivo and in vitro assays, we reveal that the enforced expression of FHIT significantly suppresses metastasis, accompanied by inhibition of the epithelial-mesenchymal transition (EMT), a process involved in metastasis through coordinate modulation of EMT-related genes. Specifically, miR-30c, a FHIT-upregulated microRNA, contributes to FHIT function in suppression of EMT and metastasis by directly targeting metastasis genes Metadherin (MTDH), High-mobility group AT-hook 2 (HMGA2), and the mesenchymal markers, Vimentin (VIM) and Fibronectin (FN1), in human lung cancer. Finally, we demonstrate that the expression pattern of FHIT and miR-30c is inversely correlated with that of MTDH and HMGA2 in normal tissue, non-metastatic and metastatic tumors, serving as a potential biomarker for metastasis in lung cancer.
Asunto(s)
Ácido Anhídrido Hidrolasas/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Ácido Anhídrido Hidrolasas/biosíntesis , Moléculas de Adhesión Celular , Línea Celular Tumoral , Fibronectinas/biosíntesis , Regulación Neoplásica de la Expresión Génica , Proteína HMGA2/biosíntesis , Humanos , Neoplasias Pulmonares/patología , Proteínas de la Membrana , MicroARNs/biosíntesis , Metástasis de la Neoplasia , Proteínas de Neoplasias/biosíntesis , Proteínas de Unión al ARN , Vimentina/biosíntesisRESUMEN
The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.
Asunto(s)
Cromosomas Humanos Par 8/genética , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , ARN Largo no Codificante/genética , Secuencia de Bases , Línea Celular Tumoral , Elementos de Facilitación Genéticos/genética , Citometría de Flujo , Humanos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Receptor IGF Tipo 1/metabolismo , Regiones no Traducidas 3' , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Genes p53 , Humanos , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Inhibidores de las Quinasa Fosfoinosítidos-3 , ARN Interferente Pequeño/genética , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/genética , Transducción de SeñalRESUMEN
In order to study the feasibility of using digital image analysis and machine learning algorithm to estimate leaf nitrogen accumulation (LNA) of winter wheat at canopy level, digital images of winter wheat canopies grown under six levels of nitrogen application rate were taken for four times during the elongation stage. Meanwhile, wheat plants were sampled to measure LNA. The random forest method using CIEL*a*b* components was used to segment wheat plant from soil background and then extract canopy cover, RGB components of sRGB color space and compute five color indices derived from RGB components. Correlation analysis was carried out to identify the relationship between LNA and canopy cover (CC), RGB components, and five color indices. Two kinds of nonlinear least squares regression models (NLS) with different independent variables of color components and color indices, and three machine learning algorithmic of artificial neural network (ANN), support vector regression (SVR), and random forests method (RF) were used to estimate winter wheat leaf nitrogen accumulation. All three machine learning algorithm had four input variables of CC, R, G, and B. The results showed that, CC, R and G component of sRGB color space, and five color indices derived from RGB components showed significant correlations with LNA during the elongation stage. CC revealed the highest correlation with LNA. The lowest accuracy in estimation LNA was achieved by using nonlinear least square model with CC and color indices, and RF had showed the problem of overfitting. The other three methods of LNA with CC and RGB components, ANN, and SVR had showed good performance with higher R2 (0.851, 0.845, and 0.862) and lower RMSE (19.440, 19.820, and 18.698) for model calibration and validation, revealing good generalization ability.
RESUMEN
In order to explore a non-destructive monitoring technique, the use of digital photo pixels canopy cover (CC) diagnosis and prediction on maize growth and its nitrogen nutrition status. This study through maize canopy digital photo images on relationship between color index in the photo and the leaf area index (LAI), shoot dry matter weight (DM), leaf nitrogen content percentage (N%). The test conducted in the Chinese Academy of Agricultural Science from 2012 to 2013, based on Maize canopy Visual Image Analysis System developed by Visual Basic Version 6.0, analyzed the correlation of CC, color indices, LAI, DM, N% on maize varieties (Zhongdan909, ZD 909) under three nitrogen levels treatments, furthermore the indicators significantly correlated were fitted with modeling, The results showed that CC had a highly significant correlation with LAI (r = 0.93, p < 0.01), DM (r = 0. 94, p < 0.01), N% (r = 0.82, p < 0.01). Estimating the model of LAI, DM and N% by CC were all power function, and the equation respectively were y = 3.281 2x(0.763 9), y = 283.658 1x(0.553 6) and y = 3.064 5x(0.932 9); using independent data from modeling for model validation indicated that R2, RMSE and RE based on 1 : 1 line relationship between measured values and simulated values in the model of CC estimating LAI were 0.996, 0.035 and 1.46%; R2, RMSE and RE in the model of CC estimating DM were 0.978, 5.408 g and 2.43%; R2, RMSE and RE in the model of CC estimating N% were 0.990, 0.054 and 2.62%. In summary, the model can comparatively accurately estimate the LAI, DM and N% by CC under different nitrogen levels at maize grain filling stage, indicating that it is feasible to apply digital camera on real-time undamaged rapid monitoring and prediction for maize growth conditions and its nitrogen nutrition status. This research finding is to be verified in the field experiment, and further analyze the applicability throughout the growing period in other maize varieties and different planting density.
Asunto(s)
Nitrógeno/análisis , Hojas de la Planta/química , Zea mays/crecimiento & desarrollo , Modelos Teóricos , Hojas de la Planta/crecimiento & desarrollo , Análisis Espectral , Zea mays/químicaRESUMEN
Digital image analysis has been widely used in non-destructive monitoring of crop growth and nitrogen nutrition status due to its simplicity and efficiency. It is necessary to segment winter wheat plant from soil background for accessing canopy cover, intensity level of visible spectrum (R, G, and B) and other color indices derived from RGB. In present study, according to the variation in R, G, and B components of sRGB color space and L*, a*, and b* components of CIEL* a* b* color space between wheat plant and soil background, the segmentation of wheat plant from soil background were conducted by the Otsu's method based on a* component of CIEL* a* b* color space, and RGB based random forest method, and CIEL* a* b* based random forest method, respectively. Also the ability to segment wheat plant from soil background was evaluated with the value of segmentation accuracy. The results showed that all three methods had revealed good ability to segment wheat plant from soil background. The Otsu's method had lowest segmentation accuracy in comparison with the other two methods. There were only little difference in segmentation error between the two random forest methods. In conclusion, the random forest method had revealed its capacity to segment wheat plant from soil background with only the visual spectral information of canopy image without any color components combinations or any color space transformation.
Asunto(s)
Análisis Espectral/métodos , Triticum/crecimiento & desarrollo , AlgoritmosRESUMEN
The objective of this study was to evaluate the feasibility of using color digital image analysis and back propagation (BP) based artificial neural networks (ANN) method to estimate above ground biomass at the canopy level of winter wheat field. Digital color images of winter wheat canopies grown under six levels of nitrogen treatments were taken with a digital camera for four times during the elongation stage and at the same time wheat plants were sampled to measure above ground biomass. Canopy cover (CC) and 10 color indices were calculated from winter wheat canopy images by using image analysis program (developed in Microsoft Visual Basic). Correlation analysis was carried out to identify the relationship between CC, 10 color indices and winter wheat above ground biomass. Stepwise multiple linear regression and BP based ANN methods were used to establish the models to estimate winter wheat above ground biomass. The results showed that CC, and two color indices had a significant cor- relation with above ground biomass. CC revealed the highest correlation with winter wheat above ground biomass. Stepwise multiple linear regression model constituting CC and color indices of NDI and b, and BP based ANN model with four variables (CC, g, b and NDI) for input was constructed to estimate winter wheat above ground biomass. The validation results indicate that the model using BP based ANN method has a better performance with higher R2 (0.903) and lower RMSE (61.706) and RRMSE (18.876) in comparation with the stepwise regression model.
Asunto(s)
Biomasa , Redes Neurales de la Computación , Triticum/crecimiento & desarrollo , Color , Nitrógeno , Análisis EspectralRESUMEN
Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo. To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.
Asunto(s)
Neoplasias Pulmonares , Tiorredoxina Reductasa 1 , Humanos , Tiorredoxina Reductasa 1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Auranofina/farmacología , Auranofina/uso terapéutico , Apoptosis , Línea Celular Tumoral , Muerte CelularRESUMEN
Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.
Asunto(s)
Artemisininas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Especies Reactivas de Oxígeno , Humanos , Apoptosis , Artemisininas/farmacología , Artemisininas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Muerte Celular , Línea Celular Tumoral , Cisplatino/farmacología , Ciclooxigenasa 1/metabolismo , Neoplasias Pulmonares/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Inhibidores de la Ciclooxigenasa/farmacologíaRESUMEN
Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Auranofina , Neoplasias del Colon , Sinergismo Farmacológico , Compuestos Heterocíclicos con 3 Anillos , Proteínas Proto-Oncogénicas c-akt , Pironas , Especies Reactivas de Oxígeno , Transducción de Señal , Tiorredoxina Reductasa 1 , Humanos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tiorredoxina Reductasa 1/metabolismo , Tiorredoxina Reductasa 1/antagonistas & inhibidores , Auranofina/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Línea Celular Tumoral , Fosforilación/efectos de los fármacos , Morfolinas/farmacología , Células HCT116RESUMEN
Nonsmall cell lung cancer (NSCLC) is one of the major causes of cancerrelated death worldwide. Cisplatin is a frontline chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatinmediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcriptionquantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROSmediated endoplasmic reticulum stress, and the CJunaminoterminal kinase and p38 mitogenactivated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROSmediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Sinergismo Farmacológico , Glucósidos , Neoplasias Pulmonares , NADPH Oxidasa 5 , Estrés Oxidativo , Especies Reactivas de Oxígeno , Estilbenos , Ensayos Antitumor por Modelo de Xenoinjerto , Cisplatino/farmacología , Cisplatino/uso terapéutico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Animales , Humanos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MasculinoRESUMEN
BACKGROUND: RNA-binding protein Quaking-5 (QKI-5), a major isoform of QKIs, inhibits tumor progression in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of QKI-5 in the cell cycle of NSCLC are still largely unknown. METHODS: MTT, flow cytometry, and colony formation assays were used to investigate cellular phenotypic changes. Mice xenograft model was used to evaluate the antitumor activities of QKI-5. Co-immunoprecipitation, RNA immunoprecipitation (RIP), and RIP sequencing were used to investigate protein-protein interaction and protein-mRNA interaction. RESULTS: The QKI-5 expression was downregulated in NSCLC tissues compared with that in paired normal adjacent lung tissues. Overexpression of QKI-5 inhibited NSCLC cell proliferative and colony forming ability. In addition, QKI-5 induced cell cycle arrest at G0/G1 phase through upregulating p21Waf1/Cip1 (p21) expression and downregulating cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 expressions. Further analyses showed that QKI-5 interacts with p21 protein and CDK4, CDK6 mRNAs, suggesting a critical function of QKI-5 in cell cycle regulation. In agreement with in vitro study, the mouse xenograft models validated tumor suppressive functions of QKI-5 in vivo through altering cell cycle G1-phase-associated proteins. Moreover, we demonstrated that QKI-5 is a direct target of miR-31. The QKI-5 expression was anticorrelated with the miR-31 expression in NSCLC patient samples. CONCLUSION: Our results suggest that the miR-31/QKI-5/p21-CDK4-CDK6 axis might have critical functions in the progression of NSCLC, and targeting this axis could serve as a potential therapeutic strategy for NSCLC.