RESUMO
Mantle cell lymphoma (MCL) pathogenesis is still partially unexplained. We investigate the importance of microRNA (miRNA) expression as an additional feature that influences MCL pathway deregulation and may be useful for predicting patient outcome. Twenty-three MCL samples, eight cell lines and appropriate controls were screened for their miRNAs and gene expression profiles and DNA copy-number changes. MCL patients exhibit a characteristic signature that includes 117 miRNA (false discovery rate <0.05). Combined analysis of miRNAs and the gene expression profile, paired with bioinformatics target prediction (miRBase and TargetScan), revealed a series of genes and pathways potentially targeted by a small number of miRNAs, including essential pathways for lymphoma survival such as CD40, mitogen-activated protein kinase and NF-kappaB. Functional validation in MCL cell lines demonstrated NF-kappaB subunit nuclear translocation to be regulated by the expression of miR-26a. The expression of 12 selected miRNAs was studied by quantitative PCR in an additional series of 54 MCL cases. Univariate analysis identified a single miRNA, miR-20b, whose lack of expression distinguished cases with a survival probability of 56% at 60 months. In summary, using a novel bioinformatics approach, this study identified miRNA changes that contribute to MCL pathogenesis and markers of potential utility in MCL diagnosis and clinical prognostication.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , MicroRNAs/fisiologia , Transcrição Gênica , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
UNLABELLED: The aim of this study was to explore differences in the cytokine profile among de novo kidney transplant recipients treated with either Rapamycin (Rapa) + cyclosporine (CsA) + prednisone (P) or CsA + azathioprine (Aza) + P. PATIENTS AND METHODS: Among the 13 adult kidney transplant recipients studied, seven received Rapa + CsA + P while the remaining six received CsA + Aza + P with their living donors serving as controls (n = 13). Spontaneous production of IL-2, IFNgamma, IL-10, and TGF-beta were measured by ELISA in supernatants from 24-hour cultured unstimulated peripheral blood mononuclear cell (PBMC) at time zero (the day before the transplant), and at 3 and 6 months posttransplant. Cytokines were also measured 1 month after CsA withdrawal in the Rapa + CsA + P group. RESULTS: From time zero to the end of the study, IL-2, IFNgamma, and IL-10 were present at low or undetectable levels in all three groups. TGF-beta tended to increase in supernatants from patients under Rapa + CsA + P at 6 months posttransplant and at 1 month after CsA withdrawal without correlation to Rapa blood levels. TGF-beta remained stable throughout the study period for patients included in the CsA + Aza + P group. There was no difference in this cytokine level between these study groups at any given time. CONCLUSIONS: This study showed no differences in the spontaneous cytokine profiles evaluated in patients treated with both therapeutic schemes.