RESUMO
We investigated the effects of histone deacetylase (HDAC) inhibitors such as sodium butyrate (SB) and trichostatin A (TSA) on the expression of vascular endothelial growth factor (VEGF) by human glioblastoma T98G, U251MG, and U87MG cells. The glioblastoma cells secreted three VEGF isoforms, VEGF (189), (165), and (121), although the expression levels of VEGF differed between the cell types. Treatment with either 5mM SB or 100 ng/ml TSA reduced VEGF secretion in conditioned media and reduced VEGF mRNA expression. We also studied the expression of VEGF-B, -C, and -D mRNA in human glioblastoma cells and their modulation by HDAC inhibitors. The PCR products of VEGF-B (357bp), VEGF-C (501bp), and VEGF-D (484bp) were amplified in all glioblastoma cells examined. Treatment with SB reduced the expression of VEGF-D mRNA in U251MG cells and the expression of VEGF-B mRNA in U87MG cells. TSA treatment reduced the expression of VEGF-D in U251MG cells. These results suggest that HDAC inhibitors reduce VEGF secretion and modulate the expression of the other VEGF family members, and therefore may inhibit angiogenesis in glioblastoma tissues.
Assuntos
Neoplasias Encefálicas/metabolismo , Butiratos/farmacologia , Fatores de Crescimento Endotelial/metabolismo , Inibidores Enzimáticos/farmacologia , Glioblastoma/metabolismo , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfocinas/metabolismo , Western Blotting , Meios de Cultivo Condicionados , Depressão Química , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that is associated with various tumors and cysts in the central nervous system (CNS) and visceral organs. Inactivation of the VHL tumor-suppressor protein and subsequent loss of function in the VHL, and Elongin BC (VBC) complex result in dysfunction in the ubiquitination of hypoxia-inducible factor (HIF), which is an important step in the development of angiogenic tumors. The most frequent disorders in VHL disease are hemangioblastoma in the CNS and retina, pheochromocytoma in the adrenal gland, renal cell carcinoma, and pancreatic neuroendocrine tumor. Here, we review recent ideas on the pathogenesis and clinical diagnosis and treatment of VHL disease. Progress in molecular diagnosis and molecular targeting therapy is expected for improvement in the diagnosis and treatment of this disease. The family's support for patients with VHL disease is important, being mutually helpful to overcome various social and psychological problems in the patients.