Peripheral neuropathy is one of the main side-effects of novel therapeutics used in oncohematological diseases, but the molecular basis underlying its development and progression as well as neurotoxicity mechanisms induced by the use of these therapeutics are still not fully elucidated. The aim of this study was to demonstrate the effect of bortezomib on global gene and miRNA expression on PC12-derived nerve cells. Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells. Analysis of functional annotations mainly identified downregulated processes (e.g., regulation of cell cycle, DNA replication and repair, regulation of cell migration, neuron projection morphogenesis and neurotransmitter secretion). The result of miRNA expression analysis demonstrated only 11 significantly downregulated miRNAs (at least two fold) in bortezomib-treated PC12-derived nerve cells vs. control cells. MiRNAs regulate gene expression, therefore we decided to conduct an analysis comparing the outcomes of miRNA microarray expression data to the obtained mRNA data. The most interesting miRNA-target gene correlation is downregulated expression of miR-130a-3p and miR-152-3p and as a result of this downregulation the expression of the Gadd45 increased. This gene is a member of a group of genes, the transcript expression of which is enhanced after stressful growth arrest conditions and treatment with DNA-damaging agents like drugs or mutagens.

译文

周围神经病变是肿瘤血液学疾病中使用的新型疗法的主要副作用之一,但其发展和进程的分子基础以及使用这些疗法引起的神经毒性机制仍未完全阐明。这项研究的目的是证明硼替佐米对PC12来源的神经细胞的整体基因和miRNA表达的影响。微阵列分析显示,与未经处理/对照的细胞相比,在用硼替佐米处理过的PC12衍生的神经细胞中,1383个基因的表达被下调了至少两倍,而671个基因被上调了至少两倍。对功能注释的分析主要确定了下调的过程(例如,细胞周期调节,DNA复制和修复,细胞迁移调节,神经元投射形态发生和神经递质分泌调节)。 miRNA表达分析的结果表明,相比于对照细胞,在硼替佐米治疗的PC12衍生的神经细胞中只有11个显着下调的miRNA(至少两倍)。 MiRNA调节基因表达,因此我们决定进行分析,将miRNA微阵列表达数据的结果与获得的mRNA数据进行比较。最有趣的miRNA-靶基因相关性是miR-130a-3p和miR-152-3p的表达下调,并且由于这种下调,Gadd45的表达也增加了。该基因是一组基因的成员,在紧张的生长停滞条件下以及用诸如药物或诱变剂之类的DNA破坏剂处理后,其转录本表达得以增强。

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