miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis
miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis
复制标题
DOI：
10.1038/onc.2012.51
复制
发表时间：
2013-01-17
期刊：
影响因子：
8
通讯作者：
de Franciscis, V.
中科院分区：
文献类型：
--
作者：
Catuogno, S.;Cerchia, L.;de Franciscis, V.
MicroRNAs （miRNAs）是一类负向调控靶基因表达的小非编码rna。它们参与了许多生物过程，包括细胞增殖、凋亡和分化，被认为是有希望的新的癌症治疗靶点。然而，参与细胞凋亡的mirna及其各自的靶点在很大程度上仍然未知。鉴于miRNA调控基因表达的复杂性升高，我们进行了功能筛选，作为鉴定肺癌细胞中可能干扰凋亡过程的miRNA的替代策略。为此，我们构建了一种非小细胞肺癌A549细胞系的衍生物，其中caspase-8（凋亡的关键上游启动物）可以通过给药小二聚体药物AP20187激活。我们发现了一些mirna可以从caspase-8激活中拯救细胞活力。它们包括已经被描述为致癌的mirna，如miR-17、miR-135和miR-520，但也包括一些mirna，如miR-124-1和miR-34c，它们的肿瘤抑制作用已经被描述或预期。其中，nniR-34c-5p显著增加对紫杉醇诱导的细胞凋亡的抗性。我们证明Bmf （bcl -2修饰因子）是miR-34c-5p的靶标，其沉默和已知的miR-34c-5p靶标c-myc的沉默通过p53下调有助于抵抗紫杉醇诱导的细胞凋亡。中华肿瘤杂志，2013,32,341-351；doi: 10.1038 / onc.2012.51;2012年2月27日在线发布
MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that negatively regulate the expression of their target genes. They are involved in many biological processes, including cell proliferation, apoptosis and differentiation, and are considered as promising new therapeutic targets for cancer. However, the identity of miRNAs involved in apoptosis and their respective targets remain largely unknown. Given the elevated complexity of miRNA regulation of gene expression, we performed a functional screening as an alternative strategy to identify those miRNAs that in lung cancer cells may interfere with the apoptotic process. To this aim, we generated a derivative of the non-small cell lung carcinoma A549 cell line in which caspase-8, a critical upstream initiator of apoptosis, can be activated by administration of the small dimerizer drug AP20187. We found a number of miRNAs that may rescue cell viability from caspase-8 activation. They included miRNAs already described as oncogenic such as miR-17, miR-135 and miR-520, but also some miRNAs such as miR-124-1 and miR-34c for which a tumor-suppressive role has instead been described or expected. Among them, nniR-34c-5p markedly increased resistance to paclitaxel-induced apoptosis. We demonstrate that Bmf (Bcl-2-modifying factor) is a target of miR-34c-5p, and that its silencing, together with that of c-myc, a known target of miR-34c-5p, contributes to resistance to apoptosis induced by paclitaxel through p53 downregulation. Oncogene (2013) 32, 341-351; doi:10.1038/onc.2012.51; published online 27 February 2012