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1.
Cancer Res ; 67(20): 9762-70, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17942906

RESUMO

Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to down-regulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers.


Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfoma de Burkitt/metabolismo , Processos de Crescimento Celular/genética , Regulação para Baixo , Inativação Gênica , Genes myc , Humanos , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos
2.
J Pediatr Surg ; 43(6): 1134-41, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18558196

RESUMO

PURPOSE: In children, therapeutic management of immunosuppression relies on allograft function, drug levels, and clinical insight. Using a Food and Drug Administration-approved test for T-cell response, T-cell activation in vitro can be measured to monitor the immune response. METHODS: In a retrospective study, 92 posttransplant children who received either a liver and/or kidney transplant and were followed by routine screening had their T-cell response tested by the Cylex ImmuKnow assay (Columbia, MD). After phytohemagglutinin-L stimulation of T-cells, adenosine triphosphate (ATP) concentrations were measured. In this assay, light emission at lambda = 562 nm is proportional to the ATP concentration (ng/mL). Immunosuppressive drug trough levels were also measured. Quantitative real-time polymerase chain reaction Epstein-Barr virus (EBV) viral titers were determined for 2 patients. RESULTS: Separating the results into younger than 12 years and 12-year or older populations, we found that for the younger than 12 years, 28% of patients were in the low immune function category, 47% in the moderate, and 25% in the high category. For the 12 years or older, 25% of patients were in the low immune function category, 47% in the moderate, and 28% in the high category. The immune function distribution was not different (P = not significant) between the younger than 12 years and 12-year or older groups. Tacrolimus trough levels were 6.3 +/- 2.4 ng/mL for younger than 12 years and 5.6 +/- 3.3 ng/mL for 12 years or older (P = not significant), and rapamycin was similar, but both showed no correlation to immune function. We observed increased ATP values with decreased EBV viral loads. CONCLUSIONS: These results suggest that tacrolimus and/or rapamycin levels do not adequately determine the biologic effect of immunosuppression. We expect that future T-cell activation monitoring will allow us to diminish rejection and infection events posttransplantation and lead to a healthier pediatric transplant population.


Assuntos
Imunossupressores/sangue , Transplante de Órgãos/efeitos adversos , Linfócitos T/citologia , Imunologia de Transplantes/fisiologia , Trifosfato de Adenosina/metabolismo , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imunoensaio/métodos , Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Transplante de Rim/imunologia , Transplante de Rim/métodos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/imunologia , Transplante de Fígado/métodos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Transplante de Órgãos/métodos , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Sirolimo/administração & dosagem , Sirolimo/sangue , Linfócitos T/efeitos dos fármacos , Tacrolimo/administração & dosagem , Tacrolimo/sangue
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