Gañán-Gómez Irene, Wei Yue, Yang Hui, Pierce Sherry, Bueso-Ramos Carlos, Calin George, Boyano-Adánez María Del Carmen, García-Manero Guillermo
Department of Systems Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2014 Apr 1;9(4):e93404. doi: 10.1371/journal.pone.0093404. eCollection 2014.
Myelodysplastic syndromes (MDS) are characterized by impaired proliferation and differentiation of hematopoietic stem cells. The participation of toll-like receptor (TLR)-mediated signaling in MDS is well documented. Increased TLR signaling leads to the constitutive activation of NF-κB, which mediates inflammation, cell proliferation and apoptosis. In addition, the TLR pathway induces the expression of miRNAs which participate in the fine-tuning of the inflammatory response. miRNAs also regulate other biological processes, including hematopoiesis. miR-125a and miR-125b are known modulators of hematopoiesis and are abnormally expressed in several hematologic malignancies. However, little is known about their role in MDS. NF-κB-activating ability has been described for both miRNAs. We studied the role of miR-125a/miR-125b in MDS and their relationship with TLR signaling and hematopoietic differentiation. Our results indicate that miR-125a is significantly overexpressed in MDS patients and correlates negatively with patient survival. Expression of miR-99b, which is clustered with miR-125a, is also directly correlated with prognosis of MDS. Both miR-125a and miR-99b activated NF-κB in vitro; however, we observed a negative correlation between miR-99b expression and the levels of TLR2, TLR7 and two downstream genes, suggesting that NF-κB activation by the miRNA cluster occurs in the absence of TLR signaling. We also show that TLR7 is negatively correlated with patient survival in MDS. In addition, our data suggest that miR-125a may act as an NF-κB inhibitor upon TLR stimulation. These results indicate that miR-125a is involved in the fine-tuning of NF-κB activity and that its effects may depend on the status of the TLR pathway. Furthermore, we observed that miR-125a inhibits erythroid differentiation in leukemia and MDS cell lines. Therefore, this miRNA could serve as a prognostic marker and a potential therapeutic target in MDS.
骨髓增生异常综合征（MDS）的特征是造血干细胞增殖和分化受损。Toll样受体（TLR）介导的信号传导参与MDS已有充分文献记载。TLR信号增加导致NF-κB的组成性激活，NF-κB介导炎症、细胞增殖和凋亡。此外，TLR途径诱导参与炎症反应微调的miRNA表达。miRNA还调节包括造血在内的其他生物学过程。miR-125a和miR-125b是已知的造血调节剂，在几种血液系统恶性肿瘤中异常表达。然而，它们在MDS中的作用知之甚少。两种miRNA均已被描述具有NF-κB激活能力。我们研究了miR-125a/miR-125b在MDS中的作用及其与TLR信号传导和造血分化的关系。我们的结果表明，miR-125a在MDS患者中显著过表达，且与患者生存率呈负相关。与miR-125a成簇的miR-99b的表达也与MDS的预后直接相关。miR-125a和miR-99b在体外均激活NF-κB；然而，我们观察到miR-99b表达与TLR2、TLR7及两个下游基因水平呈负相关，这表明miRNA簇激活NF-κB发生在无TLR信号的情况下。我们还表明，TLR7与MDS患者生存率呈负相关。此外，我们的数据表明，miR-125a在TLR刺激后可能作为NF-κB抑制剂发挥作用。这些结果表明，miR-125a参与NF-κB活性的微调，其作用可能取决于TLR途径的状态。此外，我们观察到miR-125a抑制白血病和MDS细胞系中的红系分化。因此，这种miRNA可作为MDS的预后标志物和潜在治疗靶点。
