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Mol Cancer Res ; 5(4): 383-91, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17426252

RESUMO

The androgen receptor (AR) is implicated in prostate cancer growth, progression, and angiogenesis. Hypoxia-inducible factor-1 (HIF-1), which transcriptionally regulates hypoxia-inducible angiogenic factors, is up-regulated in prostate cancers compared with adjacent normal tissues. HIF-1 may be involved in prostate cancer as well as the AR, but the involvement of HIF-1 in prostate cancer angiogenesis and progression has not been fully elucidated. In the present study, we found that in prostate cancer LNCaP cells dihydrotestosterone enhanced the expression of GLUT-1, one of the HIF-1 target genes, and also that hypoxia enhanced the expression of prostate-specific antigen (PSA) that is one of the AR target genes and is involved in tumor invasion. Small interfering RNA that specifically inhibits HIF-1 reduced the expression levels of PSA as well as GLUT-1. Reporter gene analysis showed that dihydrotestosterone activated the HIF-1-mediated gene expression and hypoxia enhanced the AR-induced promoter activity of human PSA gene. Deletion and site-directed mutation of the 5'-flanking region of human PSA gene revealed that the sequence ACGTG between -3951 and -3947 was essential in the response to hypoxia. Furthermore, chromatin immunoprecipitation assay indicated that HIF-1 interacts with the AR on the human PSA gene promoter. These results indicated that in prostate cancers, HIF-1 might cooperate with the AR to activate the expression of several genes related to tumor angiogenesis, invasion, and progression.


Assuntos
Androgênios/farmacologia , Hipóxia Celular , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Sequência de Bases , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Humanos , Masculino , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Antígeno Prostático Específico/genética , Receptores Androgênicos/metabolismo , Transfecção
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