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Genet Mol Res ; 13(3): 7173-83, 2014 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-25222223

RESUMEN

In this study, we examined the effect glucagon-induced hyperglycemia on tumor growth as well as the role of the hypoxia-inducible factor 1 (HIF-1)-vascular endothelial growth factor (VEGF) pathway in this condition. A high concentration of glucose (HG) was utilized to treat HeLa cells under hypoxic or normoxic conditions, and transcriptional levels of HIF-1, VEGF, and basic fibroblast growth factor (bFGF) were evaluated. Moreover, the ability of an HIF-1 inhibitor to block the effect induced by HG was examined. By contrast, hyperglycemia was induced in nude mice by glucagon released from an osmotic pump, and microvessel density was determined with CD31 staining. Thus, the relationship among hyperglycemia, microvessel density, tumor growth, and the HIF-1 inhibitor were analyzed. We found that HG increased transcription of the VEGF gene, which is downstream of HIF-1. Moreover, HG impaired the function of HIF-1 inhibitors [HIF-1 small interfering RNA (siRNA) and berberine] to affect the VEGF transcription level in tumor cells. By contrast, hyperglycemia increased tumor microvessel density and promoted tumor growth, which was inhibited by the HIF-1 inhibitor. However, hyperglycemia attenuated the effect of the HIF-1 inhibitor. Glucagon-induced hyperglycemia influenced tumor microenvironments through the HIF-1-VEGF-dependent pathway and promoted tumor growth and resistance to HIF-1 inhibition treatments.


Asunto(s)
Glucagón/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Glucagón/farmacología , Xenoinjertos , Humanos , Hiperglucemia/inducido químicamente , Factor 1 Inducible por Hipoxia/genética , Ratones , Ratones Desnudos , Ratones Obesos , Neoplasias/genética , Neovascularización Patológica/genética , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genética
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