RESUMO
The B-cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). By global microRNA profiling of CLL cells stimulated or not stimulated by anti-IgM, significant up-regulation of microRNAs from the miR-132~212 cluster was observed both in IGHV gene unmutated (UM) and mutated (M) CLL cells. Parallel gene expression profiling identified SIRT1, a deacetylase targeting several proteins including TP53, among the top-ranked miR-132 target genes down-regulated upon anti-IgM exposure. The direct regulation of SIRT1 expression by miR-132 was demonstrated using luciferase assays. The reduction of SIRT1 mRNA and protein (P = 0.001) upon anti-IgM stimulation was associated with an increase in TP53 acetylation (P = 0.007), and the parallel up-regulation of the TP53 target gene CDKN1A. Consistently, miR-132 transfections of CLL-like cells resulted in down-regulation of SIRT1 and an induction of a TP53-dependent apoptosis. Finally, in a series of 134 CLL samples, miR-132, when expressed above the median value, associated with prolonged time-to-first-treatment in patients with M CLL (HR = 0.41; P = 0.02). Collectively, the miR-132/SIRT1/TP53 axis was identified as a novel pathway triggered by BCR engagement that further increases the complexity of the interactions between tumor microenvironments and CLL cells.
Assuntos
Leucemia Linfocítica Crônica de Células B/metabolismo , MicroRNAs/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Estudos de Casos e Controles , Proliferação de Células/fisiologia , Genes p53 , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , MicroRNAs/genética , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais , Sirtuína 1/genética , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Regulação para CimaRESUMO
Recently it was reported that microRNA from the miR-17 ~ 92 family may have a key role in chronic lymphocytic leukemia (CLL). Here, we designed specific oligonucleotides to target endogenous miR-17 (antagomiR17). In-vitro administration of antagomiR17 effectively reduced miR-17 expression and the proliferation of CLL-like MEC-1 cells. When injected in-vivo in tumor generated by the MEC-1 cells in SCID mice, antagomiR17 dramatically reduced tumor growth and significantly increase survival. Altogether, our results provide the rationale for the use of antagomiR17 as a novel potential therapeutic tool in CLL and in other lymphoproliferative disorders where miR-17 has a driver role in tumor progression.
