miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1
miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1
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DOI：
10.1016/j.humpath.2009.02.003
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发表时间：
2009-09-01
期刊：
影响因子：
3.3
通讯作者：
Ng, Ho-keung
中科院分区：
文献类型：
--
作者：
Li, Kay Ka Wai;Pang, Jesse Chung-sean;Ng, Ho-keung
考虑到miR-124在分化和成熟的神经元和小脑外颗粒细胞中优先表达，我们研究了miR-124是否在成神经管细胞瘤的发展中发挥作用。29例髓母细胞瘤的定量表达分析显示，21例（72%）肿瘤的miR-124水平显著下调至少2倍，其中11例肿瘤的miR-124水平较正常小脑降低10倍以上（P < 0.01）。在成神经管细胞瘤细胞系ONS-76和DAOY中异位表达miR-124抑制细胞增殖。通过计算和表达分析，我们确定了溶质载体家族16，成员1 （SLC16A1）是miR-124的候选靶点。转染miR-124导致SLC16A1在转录物和蛋白水平上下调。利用克隆在SLC16A1荧光素酶基因下游的3'非翻译区进行的报告者实验显示，在miR-124存在下，荧光素酶活性降低，这有力地证明了miR-124是SLC16A1的直接调节因子。表达分析进一步显示，SLC16A1转录本在29例肿瘤中26例（90%）升高。siRNA敲低SLC16A1诱导成神经管细胞瘤细胞死亡。SLC16A1在有氧糖酵解过程中起外排乳酸的作用。我们推测，抑制SLC16A1功能导致细胞内pH降低至致死水平。总之，我们的研究表明miR-124在成神经管细胞瘤中很常见，其功能的恢复会抑制细胞增殖，这表明miR-124可能是一种生长抑制因子。我们的研究结果还提出了miR-124/SLC16A1通路可能代表恶性髓母细胞瘤治疗的新治疗靶点的可能性。(C) 2009爱思唯尔公司版权所有。
Given that miR-124 is preferentially expressed in differentiating and mature neurons and external granule cells of cerebellum are thought to be cells-of-origins of medulloblastomas, we investigated if miR-124 played a role in the development of medulloblastomas. Quantitative expression analysis of 29 medulloblastomas demonstrated significant down-regulation of miR-124 in 21 (72%) tumors by at least 2-fold, with 11 of them exhibiting greater than 10-fold reduced level compared to normal cerebella (P < .01). Ectopic expression of miR-124 in medulloblastoma cell lines, ONS-76 and DAOY, inhibited cell proliferation. Using computational and expression analyses, solute carrier family 16, member 1 (SLC16A1) was identified as a candidate target of miR-124. Transfection of miR-124 resulted in down-regulation of SLC16A1 at both transcript and protein levels. Reporter assay with 3' untranslated region of SLC16A1 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-124, providing strong evidence that miR-124 is a direct regulator of SLC16A1. Expression analysis further revealed that SLC16A1 transcript was elevated in 26 (90%) of 29 tumors examined. Knockdown of SLC16A1 by siRNA induced cell death in medulloblastoma cells. SLC16A1 functions to efflux lactic acid during aerobic glycolysis. We speculated that inhibition of SLC16A1 function resulted in a decrease of intracellular pH to a lethal level. In conclusion, our study demonstrates that miR-124 deregulation is common in medulloblastomas, and restoration of its function inhibits cell proliferation, suggesting that miR-124 may act as a growth suppressor. Our findings also raise the possibility that the miR-124/SLC16A1 pathway may represent a novel therapeutic target for treatment of malignant medulloblastomas. (C) 2009 Elsevier Inc. All rights reserved.