RESUMEN

In this study, We aim to explore the association between the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), lymphocyte to monocyte ratio (LMR) and prognostic nutritional index (PNI) and distant metastasis of gastric cancer and develop an efficient nomogram for screening patients with distant metastasis. A total of 1281 inpatients with gastric cancer were enrolled and divided into the training and validation set.Univariate, Lasso regression and Multivariate Logistic Regression Analysis was used to identify the risk factors of distant metastasis. The independent predictive factors were then enrolled in the nomogram model. The nomogram's predictive perform and clinical practicality was evaluated by receiver operating characteristics (ROC) curves, calibration curves and decision curve analysis. Multivariate Logistic Regression Analysis identified D-dimer, CA199, CA125, NLR and PNI as independent predictive factors. The area under the curve of our nomogram based on these factors was 0.838 in the training cohort and 0.811 in the validation cohort. The calibration plots and decision curves demonstrated the nomogram's good predictive performance and clinical practicality in both training and validation cohort. Therefore,our nomogram could be an important tool for clinicians in screening gastric cancer patients with distant metastasis.

Asunto(s)

Linfocitos , Neutrófilos , Nomogramas , Evaluación Nutricional , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/sangre , Masculino , Femenino , Neutrófilos/patología , Persona de Mediana Edad , Linfocitos/patología , Pronóstico , Anciano , Curva ROC , Metástasis de la Neoplasia , Recuento de Linfocitos , Factores de Riesgo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Adulto , Antígeno Ca-125/sangre , Antígenos de Carbohidratos Asociados a Tumores

RESUMEN

Flotillin-1 (FLOT1) is a member of the flotillin family and serves as a hallmark of lipid rafts involved in the process of signaling transduction and vesicular trafficking. Here, we find FLOT1 promotes gastric cancer cell progression and metastasis by interacting with BCAR1, through ERK signaling. FLOT1 regulates BCAR1 phosphorylation and translocation. Overexpression of FLOT1 increases, while knockdown of FLOT1 decreases gastric cancer cell proliferation, migration and invasion. BCAR1 knockdown could block FLOT1 induced gastric cancer cell proliferation, migration and invasion. Re-expression of wildtype rather than mutant BCAR1 (Y410F) could partially restore FLOT1 knockdown induced gastric cancer cell migration and invasion, while the restore could be inhibited by ERK inhibitor. Furthermore, FLOT1 and BCAR1 expression is closely related to gastric cancer patients' poor outcome. Thus, our findings confirm that BCAR1 mediates FLOT1 induced gastric cancer progression and metastasis through ERK signaling, which may provide a novel pathway for gastric cancer treatment.

Asunto(s)

Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Línea Celular Tumoral , Transducción de Señal/genética , Proteínas de la Membrana/metabolismo , Proteína Sustrato Asociada a CrK/metabolismo

RESUMEN

Pre-mRNA processing factor 19 (PRPF19) is a multifaceted protein and participates in DNA damage response and pre-mRNA processing. The role of PRPF19 in cancer is unclear. Here, we report that the expression of PRPF19 in human tongue cancer is associated with unfavorable prognosis. Overexpression of PRPF19 promotes while knockdown of PRPF19 inhibits tongue cancer cell migration, proliferation, and tumor growth. Overexpression of PRPF19 increases the resistance of tongue cancer cells to radiation and cisplatin treatment. Furthermore, PRPF19 regulates the expression of solute carrier family 40 member 1 (SLC40A1) and mono-ADP ribosylhydrolase 2 (MACROD2), knockdown of SLC40A1 or MACROD2 decreases the sensitivity of tongue cancer cells to radiation and cisplatin treatment. Thus, our results establish a key role of PRPF19 in tongue cancer growth and chemoradiotherapy resistance, targeting PRPF19 would be an effective therapeutic strategy for tongue cancer, especially for those resistant to chemoradiotherapy.

Asunto(s)

Movimiento Celular , Proliferación Celular , Quimioradioterapia , Cisplatino/farmacología , Enzimas Reparadoras del ADN/metabolismo , Resistencia a Antineoplásicos , Proteínas Nucleares/metabolismo , Factores de Empalme de ARN/metabolismo , Tolerancia a Radiación , Neoplasias de la Lengua , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Enzimas Reparadoras del ADN/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de la radiación , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Factores de Empalme de ARN/genética , Tolerancia a Radiación/efectos de los fármacos , Tolerancia a Radiación/efectos de la radiación , Radiación Ionizante , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/terapia , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2-YES1-ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2-YES1-ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

Asunto(s)

Anexina A2/metabolismo , Proteínas Proto-Oncogénicas c-yes/metabolismo , Receptor EphA2/metabolismo , Neoplasias Gástricas/patología , Animales , Anexina A2/genética , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Fosforilación , Proteínas Proto-Oncogénicas c-yes/genética , Receptor EphA2/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Arginase I (ARG1) is a cytosolic enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The association of ARG1 with cancer has mostly been focused on the ARG1 released by tumor-associated myeloid cells in tumor microenvironment. However, the role of ARG1 expressed in cancer cells is unclear. Here, we showed that the expression of ARG1 in human breast cancer (BC) is related to a good prognosis in BC patients. Overexpression of ARG1 suppresses BC cell proliferation and migration in vitro and xenograft tumor growth and development in mouse models. Furthermore, ARG1 expression down-regulates the expression of p-AKT, leading to the de-activation of AKT signal pathway in BC cells. Thus, our results established that in contrast to the role of ARG1 released from tumor-associated myeloid cells in tumor microenvironment that promotes tumor immune escape, ARG1 expressed in BC cells suppresses AKT signaling pathway and functions as a tumor suppressor.

Asunto(s)

Arginasa/biosíntesis , Arginasa/genética , Neoplasias de la Mama/metabolismo , Animales , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Genes Supresores de Tumor , Xenoinjertos/patología , Xenoinjertos/trasplante , Humanos , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética

RESUMEN

Stress granules (SGs) are sites of mRNA storage that are formed in response to various conditions of stress, including viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. In this study, we found that infection of PRRSV strain WUH3 (genotype 2 PRRSV) induced stable formation of robust SGs in MARC-145 cells, as demonstrated by the recruitment of marker proteins of SGs, including TIA1, G3BP1, and eIF3η. Treatment with specific inhibitors or siRNAs against the stress kinases that are involved in SG formation revealed that PRRSV induced SG formation through a PERK (protein kinase R-like endoplasmic reticulum kinase)-dependent mechanism. Impairment of SG assembly by concomitant knockdown of the SG marker proteins (TIA1, G3BP1, and TIAR) did not affect PRRSV growth, while significantly enhanced PRRSV-induced NF-κB subunit p65 phosphorylation and inflammatory cytokine production. Taken together, our results demonstrate that PRRSV induces SG formation via a PERK-dependent pathway and that SGs are involved in the signaling pathway of the PRRSV-induced inflammatory response in MARC-145 cells.

Asunto(s)

Gránulos Citoplasmáticos/metabolismo , Retículo Endoplásmico/enzimología , Interacciones Huésped-Patógeno , Virus del Síndrome Respiratorio y Reproductivo Porcino/crecimiento & desarrollo , eIF-2 Quinasa/metabolismo , Animales , Línea Celular , Chlorocebus aethiops

RESUMEN

Porcine bocavirus (PBoV), a newly identified parvovirus in the family Parvoviridae, has been reported worldwide in swine with post-weaning multisystemic wasting syndrome, respiratory disease or diarrhoea and in asymptomatic swine. NP1 is a protein unique to the genus Bocavirus and its function is not fully understood. In this study, we show that the N-terminal region of PBoV NP1 contains two classical nuclear localization signals (cNLSs) and a non-classical NLS. The N-terminal region also inhibits the promoter activity of IFN-ß and IFN-stimulated response element activity the same as full-length NP1 protein, but the PBoV NP1 C-terminal region does not. PBoV NP1 also induces NFκB activation by increasing the phosphorylation of p65, and we demonstrate that the C-terminal region (aa 168-218) is responsible for the induction of NFκB, although the cNLS region of NP1 enhances this activation. The data suggest that PBoV NP1 contains two functionally independent domains in its N- and C-terminal regions. Thus, the N-terminal region of PBoV NP1 is critical for its nuclear localization and IFN-related promoter inhibition, and the C-terminal region is critical for its induction of NFκB.

Asunto(s)

Bocavirus/metabolismo , Regulación Viral de la Expresión Génica/fisiología , Enfermedades de los Porcinos/virología , Transporte Activo de Núcleo Celular/fisiología , Animales , Bocavirus/genética , Línea Celular , Humanos , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , FN-kappa B , Señales de Localización Nuclear/genética , Señales de Localización Nuclear/metabolismo , Regiones Promotoras Genéticas , Porcinos

RESUMEN

Quantum dots (QDs) have become one of the most promising luminescent materials for tracking viral infection in living cells. However, several issues regarding how QDs interact with the virus remain unresolved. Herein, the effects of Glutathione (GSH) capped CdTe QDs on virus were investigated by using pseudorabies virus (PRV) as a model. One-step growth curve and fluorescence colocalization analyses indicate that CdTe QDs inhibit PRV multiplication in the early stage of virus replication cycle by suppressing the invasion, but have no significant effect on the PRV penetration. Fluorescence spectrum analysis indicates that the size of QDs is reduced gradually after the addition of PRV within 30 min. Release of Cd(2+) was detected during the interaction of QDs and PRV, resulting in a decreased number of viruses which can infect cells. Further Raman spectra and Circular Dichroism (CD) spectroscopy analyses reveal that the structure of viral surface proteins is altered by CdTe QDs adsorbed on the virus surface, leading to the inhibition of virus replication. This study facilitates an in-depth understanding of the pathogenic mechanism of viruses and provides a basis for QDs-labeled virus research.

Asunto(s)

Compuestos de Cadmio , Glutatión , Herpesvirus Suido 1 , Puntos Cuánticos , Telurio , Animales , Compuestos de Cadmio/química , Compuestos de Cadmio/toxicidad , Línea Celular , Glutatión/química , Herpesvirus Suido 1/efectos de los fármacos , Herpesvirus Suido 1/fisiología , Tamaño de la Partícula , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Puntos Cuánticos/ultraestructura , Espectrometría de Fluorescencia , Espectrometría Raman , Electricidad Estática , Porcinos , Telurio/química , Telurio/toxicidad , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacos

RESUMEN

To subvert host antiviral immune responses, many viruses have evolved countermeasures to inhibit IFN signaling pathway. Porcine bocavirus (PBoV), a newly identified porcine parvovirus, has received attention because it shows clinically high co-infection prevalence with other pathogens in post-weaning multisystemic wasting syndrome (PWMS) and diarrheic piglets. In this study, we screened the structural and non-structural proteins encoded by PBoV and found that the non-structural protein NP1 significantly suppressed IFN-stimulated response element (ISRE) activity and subsequent IFN-stimulated gene (ISG) expression. However, NP1 affected neither the activation and translocation of STAT1/STAT2, nor the formation of the heterotrimeric transcription factor complex ISGF3 (STAT1/STAT2/IRF9). Detailed analysis demonstrated that PBoV NP1 blocked the ISGF3 DNA-binding activity by combining with the DNA-binding domain (DBD) of IRF9. In summary, these results indicate that PBoV NP1 interferes with type I IFN signaling pathway by blocking DNA binding of ISGF3 to attenuate innate immune responses.

Asunto(s)

Bocavirus/fisiología , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Interferones/metabolismo , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Proteínas no Estructurales Virales/metabolismo , Transporte Activo de Núcleo Celular , Animales , Línea Celular , ADN/metabolismo , Humanos , Factor 3 de Genes Estimulados por el Interferón/metabolismo , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/química , Modelos Biológicos , Fosforilación , Unión Proteica , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/metabolismo , Porcinos

RESUMEN

The stimulator of interferon genes (STING) of human/mouse has been identified recently as an adaptor that links virus-sensing receptors to interferon regulatory factor 3 (IRF3) activation. Here we report the cloning and characterization of porcine STING (poSTING). The full-length poSTING cDNA sequence encodes 378 amino acids and contains one endoplasmic reticulum (ER) retention motif, RAR. Phylogenetic analysis revealed that poSTING, together with bovine STING, is more closely related to the human than to mouse STING. poSTING mRNA expression was mainly detected in the spleen, lymph node and lung. Enhanced green fluorescence protein (EGFP)-labeled poSTING was found to reside predominantly in the ER, and also in the mitochondrial membrane in PK-15 cells. Over-expression of poSTING activated both IRF3 and nuclear factor kappaB (NF-kappaB) transcription factors to induce IFN-beta production, while knockdown of poSTING significantly inhibited poly(I:C)- and poly(dAT:dAT)-induced IFN-beta promoter activation and IFN-beta mRNA production. Furthermore, the pseudorabies virus (PRV), a dsDNA virus, has been shown to activate the IFN-beta promoter in a poSTING-dependent way in porcine cell lines. Altogether, these results indicate that STING is an important regulator of porcine innate immune signaling. The results will help better understand the biological role(s) of STING in innate immunity during evolution.

Asunto(s)

Herpesvirus Suido 1/inmunología , Factores Reguladores del Interferón/metabolismo , Interferón beta/biosíntesis , Proteínas de la Membrana/metabolismo , Seudorrabia/inmunología , Porcinos/inmunología , Secuencia de Aminoácidos , Animales , Bovinos , Línea Celular , Clonación Molecular , Retículo Endoplásmico/metabolismo , Herpesvirus Suido 1/patogenicidad , Humanos , Inmunidad Innata , Factor 3 Regulador del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Interferón beta/genética , Interferón beta/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Datos de Secuencia Molecular , Seudorrabia/genética , Seudorrabia/metabolismo , ARN Interferente Pequeño/genética , Alineación de Secuencia , Transducción de Señal/genética , Bazo/metabolismo , Porcinos/genética

RESUMEN

The DNA-dependent activator of IFN-regulatory factors (DAI) is a recently identified DNA sensor for intracellular DNA that triggers a signal for the production of type I IFN. Here we report the cloning and characterization of porcine DAI (poDAI). The full-length of poDAI encodes 439 amino acids, contains two N-terminal DNA-binding domains and shows similarity to mouse, rat, dog, monkey, human, horse and cattle counterparts ranging from 44% to 67%. poDAI mRNA expression was mainly detected in spleen, lung, kidney and small intestine. Over-expression of poDAI activated transcription factors IRF3 and NF-kappaB and induced IFN-beta in different porcine cell lines, but to varying degrees. Deletion mutant analysis revealed that both the DNA-binding domains and the C-terminus are required for full activation of IFN-beta. siRNA targeting poDAI significantly decreased poly(dAT:dAT)- or Pseudorabies virus (PRV)-induced IFN-beta activation. These results indicate that DAI is an important immuno-regulator of the porcine innate immune system.

Asunto(s)

Transducción de Señal/inmunología , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Western Blotting , Bovinos , Clonación Molecular , Perros , Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Interferón beta , Ratones , Datos de Secuencia Molecular , FN-kappa B/inmunología , FN-kappa B/metabolismo , Filogenia , Interferencia de ARN , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Porcinos , Transfección , eIF-2 Quinasa/inmunología