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首页> 外文期刊>BMC Genomics >miR-296-3p, miR-298-5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic α cells to cytokine-induced apoptosis as compared to β cells
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miR-296-3p, miR-298-5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic α cells to cytokine-induced apoptosis as compared to β cells

机译：与β细胞相比，miR-296-3p，miR-298-5p及其下游网络与哺乳动物胰腺α细胞对细胞因子诱导的凋亡的更高抗性有关

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Background The molecular bases of mammalian pancreatic α cells higher resistance than β to proinflammatory cytokines are very poorly defined. MicroRNAs are master regulators of cell networks, but only scanty data are available on their transcriptome in these cells and its alterations in diabetes mellitus. Results Through high-throughput real-time PCR, we analyzed the steady state microRNA transcriptome of murine pancreatic α (αTC1-6) and β (βTC1) cells: their comparison demonstrated significant differences. We also characterized the alterations of αTC1-6 cells microRNA transcriptome after treatment with proinflammatory cytokines. We focused our study on two microRNAs, miR-296-3p and miR-298-5p, which were: (1) specifically expressed at steady state in αTC1-6, but not in βTC1 or INS-1 cells; (2) significantly downregulated in αTC1-6 cells after treatment with cytokines in comparison to untreated controls. These microRNAs share more targets than expected by chance and were co-expressed in αTC1-6 during a 6–48 h time course treatment with cytokines. The genes encoding them are physically clustered in the murine and human genome. By exploiting specific microRNA mimics, we demonstrated that experimental upregulation of miR-296-3p and miR-298-5p raised the propensity to apoptosis of transfected and cytokine-treated αTC1-6 cells with respect to αTC1-6 cells, treated with cytokines after transfection with scramble molecules. Both microRNAs control the expression of IGF1Rβ, its downstream targets phospho-IRS-1 and phospho-ERK, and TNFα. Our computational analysis suggests that MAFB (a transcription factor exclusively expressed in pancreatic α cells within adult rodent islets of Langerhans) controls the expression of miR-296-3p and miR-298-5p. Conclusions Altogether, high-throughput microRNA profiling, functional analysis with synthetic mimics and molecular characterization of modulated pathways strongly suggest that specific downregulation of miR-296-3p and miR-298-5p, coupled to upregulation of their targets as IGF1Rβ and TNFα, is a major determinant of mammalian pancreatic α cells resistance to apoptosis induction by cytokines.
机译：背景哺乳动物胰腺α细胞对促炎细胞因子的抵抗力比β高，其分子基础的定义非常差。 MicroRNA是细胞网络的主要调节物，但是在这些细胞中的转录组及其在糖尿病中的改变方面只有很少的数据。结果通过高通量实时PCR，我们分析了鼠胰腺α（αTC1-6）和β（βTC1）细胞的稳态microRNA转录组：它们的比较显示出显着差异。我们还表征了促炎细胞因子治疗后αTC1-6细胞microRNA转录组的变化。我们将研究重点放在了两个microRNA上，即miR-296-3p和miR-298-5p，它们分别是：（1）在稳定状态下在αTC1-6中特异性表达，但在βTC1或INS-1细胞中不特异性表达; （2）与未处理的对照组相比，用细胞因子处理后的αTC1-6细胞明显下调。这些microRNA共享比偶然预期更多的靶标，并在6至48小时的细胞因子治疗过程中在αTC1-6中共表达。编码它们的基因在小鼠和人类基因组中物理聚集。通过利用特定的microRNA模仿物，我们证明了miR-296-3p和miR-298-5p的实验上调提高了转染和细胞因子处理的αTC1-6细胞相对于αTC1-6细胞（在经过细胞因子处理后）凋亡的倾向。用争夺分子转染。两种microRNA均控制IGF1Rβ的表达，其下游靶标是磷酸-IRS-1和磷酸-ERK，以及TNFα。我们的计算分析表明，MAFB（朗格汉斯成年啮齿动物胰岛中仅在胰腺α细胞中表达的转录因子）控制miR-296-3p和miR-298-5p的表达。结论总的来说，高通量的microRNA分析，具有合成模拟物的功能分析和调控途径的分子表征强烈表明，miR-296-3p和miR-298-5p的特异性下调，以及其靶标IGF1Rβ和TNFα的上调，是哺乳动物胰腺α细胞对细胞因子诱导的凋亡诱导抗性的主要决定因素。

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