RESUMEN
MicroRNAs play an important role in tumor development and progression. Tumor growth is closely associated with glucose metabolism. Specifically, tumor cells produce energy (ATP) under aerobic and anaerobic conditions through glycolysis and metabolites, such as lactic acid and ATP, as a result of the Warburg effect. However, the transport of glucose into cells depends on protein transporters in the cell membrane. Therefore, this area has recently become a topic of interest for research on targeted cancer therapy. We found that miRNA-451 inhibits the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway to modify the biological behavior of glioma cells. Inhibiting the PI3K/Akt pathway may prevent glucose-addicted cancer cells from performing glycolysis. Akt directly affects glycolysis by regulating the localization of the glucose transporter 1 (GLUT1). However, how miRNA-451 regulates glucose transporters on the cell membrane and affects the regulatory mechanisms of glucose metabolism in glioma cells remains unclear. Consequently, we predict and verify related gene protein interactions. By targeting CAB 39, miRNA-451 likely triggers the LKB1/AMPK/PI3K/AKT pathway, which regulates GLUT1, to inhibit the glucose metabolism of, reduce the energy supply to, and inhibit the proliferation and invasion of glioma cells. Our results suggest a new direction for the treatment of glioma.
Asunto(s)
Movimiento Celular , Proliferación Celular , Glioma/patología , Transportador de Glucosa de Tipo 1/metabolismo , MicroARNs/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Glucólisis , Humanos , Técnicas para Inmunoenzimas , Ácido Láctico/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
MicroRNAs (miRNAs) are widely expressed and regulate most biological functions. According to several research groups, miR-451 expression is decreased in glioma cells. A previous study also confirmed that miRNA-451 inhibits the PI3K/AKT signaling pathway by directly targeting CAB39, which inhibits glioma cell growth and proliferation and induces apoptosis. However, the specific regulatory mechanism is unclear. Mammalian target of rapamycin (mTOR) is a central regulator of the differentiation, proliferation, and migration of a variety of cells. Hypoxia-inducible factor (HIF)-1α is involved in tumor cell migration and invasion. Close relationships among VEGF overexpression, tumor progression, and poor clinical outcomes have been reported. However, whether miRNA-451 influences glioma cell proliferation and invasion by regulating mTOR, HIF-1α, and VEGF expression remains unknown. This study aimed to assess the effects of miRNA-451 on glioma cell proliferation and invasion in vivo and in vitro by investigating its mechanism. Related gene-protein interactions were also predicted and verified. By targeting CAB39, miRNA-451 likely represses the mTOR/HIF-1α/VEGF pathway to inhibit glioma cell proliferation and invasion. Reverse transcription polymerase chain reaction confirmed that transfection of glioma cells with a lentivirus containing miRNA-451 elevated the expression level of miR-451. Upregulation of miR-451 expression suppressed the growth and invasion of glioma cells in vitro and in vivo by targeting CAB39 and modulating the mTOR/HIF-1α/VEGF signaling pathway. Based on these results, miR-451 suppresses glioma cell proliferation and invasion in vitro and in vivo via suppression of the mTOR/HIF-1α/VEGF signaling pathway by targeting CAB39. Therefore, miR-451 may be a new target for glioma treatment.
Asunto(s)
Proteínas de Unión al Calcio/genética , Terapia Genética , Glioma/genética , MicroARNs/genética , Animales , Apoptosis/genética , Proteínas de Unión al Calcio/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Glioma/terapia , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Invasividad Neoplásica/genética , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Factor A de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Since 2000, the phenology has advanced in some years and at some locations on the Qinghai-Tibetan Plateau, whereas it has been delayed in others. To understand the variations in spring vegetation growth in response to climate, we conducted both regional and experimental studies on the central Qinghai-Tibetan Plateau. We used the normalized difference vegetation index to identify correlations between climate and phenological greening, and found that greening correlated negatively with winter-spring time precipitation, but not with temperature. We used open top chambers to induce warming in an alpine meadow ecosystem from 2012 to 2014. Our results showed that in the early growing season, plant growth (represented by the net ecosystem CO2 exchange, NEE) was lower in the warmed plots than in the control plots. Late-season plant growth increased with warming relative to that under control conditions. These data suggest that the response of plant growth to warming is complex and non-intuitive in this system. Our results are consistent with the hypothesis that moisture limitation increases in early spring as temperature increases. The effects of moisture limitation on plant growth with increasing temperatures will have important ramifications for grazers in this system.