Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury.
Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury.
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DOI：
10.1177/17590914211042220
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发表时间：
2021-01
期刊：
影响因子：
4.7
通讯作者：
Dutta R
中科院分区：
文献类型：
--
作者：
Baltan S;Sandau US;Brunet S;Bastian C;Tripathi A;Nguyen H;Liu H;Saugstad JA;Zarnegarnia Y;Dutta R
我们先前已经证明，两种抗癌药物CX-4945和MS-275可以保护和保存白质(WM)结构，并改善WM缺血损伤模型的功能恢复。虽然这两种化合物都促进恢复，但CX-4945是选择性酪蛋白激酶2(CK2)抑制剂，MS-275是选择性I类组蛋白脱乙酰酶(HDAC)抑制剂。MicroRNAs(MiRNAs)的改变介导了这些药物的一些保护作用。在这项研究中，我们的目标是(1)鉴定在小鼠视神经(MON)中表达的miRNAs；(2)确定哪些miRNAs受到氧糖剥夺(OGD)的调节；(3)确定CX-4945和MS-275处理对miRNA表达的影响。从对照组和OGD处理组动物的MON中提取RNA，分别使用CX-4945或MS-275处理和不使用CX-4945或MS-275处理的动物，使用NanoStringnCounter®miRNA表达谱进行定量。对实验组的比较分析表明，12个miRNAs在MON中高水平表达。与对照组相比，OGD上调了5个miRNAs(miR-1959、miR-501-3p、miR-146b、miR-201和miR-335-3p)，下调了2个miRNAs(miR-1937a和miR-1937b)。与单独使用OGD相比，CX-4945上调了miR-1937a和miR-1937b，下调了miR-501-3p、miR-200a、miR-1959和miR-654-3p的表达。与单纯OGD相比，MS-275上调了miR-2134、miR-2141、miR-2133、miR-34b-5p、miR-153、miR-487b、miR-376b，下调了miR-717、miR-190、miR-27a、miR-1959、miR-200a、miR-501-3p和miR-200c的表达。有趣的是，miR-501-3p和miR-1959是仅有的受OGD上调，并被OGD加CX-4945和MS-275下调的miRNAs。因此，我们认为CX-4945或MS-275对WM损伤的保护作用可能部分是通过miRNA的表达来实现的。
We have previously shown that two anti-cancer drugs, CX-4945 and MS-275, protect and preserve white matter (WM) architecture and improve functional recovery in a model of WM ischemic injury. While both compounds promote recovery, CX-4945 is a selective Casein kinase 2 (CK2) inhibitor and MS-275 is a selective Class I histone deacetylase (HDAC) inhibitor. Alterations in microRNAs (miRNAs) mediate some of the protective actions of these drugs. In this study, we aimed to (1) identify miRNAs expressed in mouse optic nerves (MONs); (2) determine which miRNAs are regulated by oxygen glucose deprivation (OGD); and (3) determine the effects of CX-4945 and MS-275 treatment on miRNA expression. RNA isolated from MONs from control and OGD-treated animals with and without CX-4945 or MS-275 treatment were quantified using NanoString nCounter® miRNA expression profiling. Comparative analysis of experimental groups revealed that 12 miRNAs were expressed at high levels in MONs. OGD upregulated five miRNAs (miR-1959, miR-501-3p, miR-146b, miR-201, and miR-335-3p) and downregulated two miRNAs (miR-1937a and miR-1937b) compared to controls. OGD with CX-4945 upregulated miR-1937a and miR-1937b, and downregulated miR-501-3p, miR-200a, miR-1959, and miR-654-3p compared to OGD alone. OGD with MS-275 upregulated miR-2134, miR-2141, miR-2133, miR-34b-5p, miR-153, miR-487b, miR-376b, and downregulated miR-717, miR-190, miR-27a, miR-1959, miR-200a, miR-501-3p, and miR-200c compared to OGD alone. Interestingly, miR-501-3p and miR-1959 were the only miRNAs upregulated by OGD, and downregulated by OGD plus CX-4945 and MS-275. Therefore, we suggest that protective functions of CX-4945 or MS-275 against WM injury maybe mediated, in part, through miRNA expression.
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