RESUMEN
BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in China. Most GC patients are diagnosed at an advanced stage, for that the prognosis is dismal and metastasis is common. Although there have been increasing numbers of studies indicating that Ubenimex can suppress metastasis in GC, the underlying mechanism is still unknown. METHODS: Herein, the inhibitory effect of Ubenimex on GC metastasis, in which the underlining mechanism was determined using Gene chip analysis, high content screening (HCS), transwell assays, wound healing assays and Western blot assays. RESULTS: The results obtained from wound healing assays and transwell assays indicated that Ubenimex, an inhibitor of CD13, suppressed the migration and invasion of MKN-28, MGC-803, BGC-823 and SGC-790 cells, by downregulating CD13 expression. In addition, the findings acquired from Gene chip analysis and HCS demonstrated that NGFI-A-binding protein 1 (NAB1) was a putative target downstream of CD13. Furthermore, the results obtained from Western blot assays showed that Ubenimex not only inhibits NAB1 expression by targeting CD13, but also inhibits GC metastasis by mitigating the activity of the MAPK signaling pathway. These findings indicated a possible mechanism via the CD13/NAB1/MAPK pathway of which activity was restrained. CONCLUSION: Ubenimex exert the inhibitory effect on GC metastasis by targeting CD13, in which NAB1 expression and the activation of MAPK signaling pathway were both suppressed. This study identified a promising target for the inhibition of GC metastasis.
RESUMEN
Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT) because of various hematologic problems, including myelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein (NAB1) to induce myelosuppression of uninfected CD34+ hematopoietic progenitor cells (HPCs) through an increase in TGF-ß production. Infection of HPCs with an HCMVΔmiR-US5-2 mutant resulted in decreased TGF-ß expression and restoration of myelopoiesis. In contrast, we show that infected HPCs are refractory to TGF-ß signaling as another HCMV miRNA, miR-UL22A, downregulates SMAD3, which is required for maintenance of latency. Our data suggest that latently expressed viral miRNAs manipulate stem cell homeostasis by inducing secretion of TGF-ß while protecting infected HPCs from TGF-ß-mediated effects on viral latency and reactivation. These observations provide a mechanism through which HCMV induces global myelosuppression following HSCT while maintaining lifelong infection in myeloid lineage cells.
Asunto(s)
Citomegalovirus , Células Madre Hematopoyéticas/virología , MicroARNs/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Latencia del Virus , Antígenos CD34/metabolismo , Células Cultivadas , Citomegalovirus/genética , Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/metabolismo , Regulación hacia Abajo , Células HEK293 , Células Madre Hematopoyéticas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Células Mieloides/metabolismo , Células Mieloides/virología , Proteínas Represoras/metabolismo , Transducción de Señal , Proteína smad3/metabolismo , Activación Viral , Latencia del Virus/genética , Latencia del Virus/fisiologíaRESUMEN
Following peripheral nerve injury, Schwann Cells (SCs) undergo dedifferentiation, proliferation, migration, and remyelination. Recent works demonstrated the importance of the short non-coding RNA (miRNAs) in SC dedifferentiation and remyelination after nerve injury. Previously, we found some miRNAs like miR-9, miR-221, miR-222 and miR-182 could regulate the proliferation and migration of SCs. Therefore, it is imperative to ask whether these miRNAs could regulate the myelination of SCs. Here we demonstrated that miR-221-3p could inhibit the myelination of SCs when co-cultured with dorsal root ganglion cells in vitro. In addition, NGF1-A binding protein 1 (Nab1) which was essential for SCs myelination could be downregulated by miR-221-3p. Suppressing the expression of Nab1 could reverse the promotion of miR-221-3p antagomir on SC myelination. The effects of miR-221-3p on SC myelination might be used to improve peripheral nerve regeneration, thus offering a new approach to peripheral nerve repair.
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MicroARNs/metabolismo , Células de Schwann/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Técnicas de Cocultivo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , MicroARNs/administración & dosificación , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos del Sistema Nervioso Periférico/administración & dosificación , Distribución Aleatoria , Ratas Sprague-Dawley , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Células de Schwann/efectos de los fármacos , Células de Schwann/patología , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/patologíaRESUMEN
Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p=1.20×10(-8), FHS p=0.05 for trochanter BMD; rs9287237, discovery p=3.55×10(-7), FHS p=9.20×10(-3) for trochanter BMD, GEFOS p=0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p=7.48×10(-7), FHS p=0.10 for inter-trochanter BMD, GEFOS p=0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p=3.09×10(-6), FHS p=8.50×10(-3), GEFOS p=1.23×10(-24) for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p=1.64×10(-6), GEFOS p=1.69×10(-3) for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p=8.79×10(-7), GEFOS p=2.61×10(-7) for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.
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Densidad Ósea/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 2/genética , Estudio de Asociación del Genoma Completo , Cadera/fisiopatología , Adulto , Femenino , Redes Reguladoras de Genes , Sitios Genéticos , Cadera/patología , Humanos , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los ResultadosRESUMEN
The unicellular green alga Chlamydomonas reinhardtii is capable of using organic and inorganic carbon sources simultaneously, which requires the adjustment of photosynthetic activity to the prevailing mode of carbon assimilation. We obtained novel insights into the regulation of light-harvesting at photosystem II (PSII) following altered carbon source availability. In C. reinhardtii, synthesis of PSII-associated light-harvesting proteins (LHCBMs) is controlled by the cytosolic RNA-binding protein NAB1, which represses translation of particular LHCBM isoform transcripts. This mechanism is fine-tuned via regulation of the nuclear NAB1 promoter, which is activated when linear photosynthetic electron flow is restricted by CO(2)-limitation in a photoheterotrophic context. In the wild-type, accumulation of NAB1 reduces the functional PSII antenna size, thus preventing a harmful overexcited state of PSII, as observed in a NAB1-less mutant. We further demonstrate that translation control as a newly identified long-term response to prolonged CO(2)-limitation replaces LHCII state transitions as a fast response to PSII over-excitation. Intriguingly, activation of the long-term response is perturbed in state transition mutant stt7, suggesting a regulatory link between the long- and short-term response. We depict a regulatory circuit operating on distinct timescales and in different cellular compartments to fine-tune light-harvesting in photoheterotrophic eukaryotes.