Identification of hypoxia-inducible factor-1α as a novel target for miR-17-92 microRNA cluster
Identification of hypoxia-inducible factor-1α as a novel target for miR-17-92 microRNA cluster
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DOI：
10.1158/0008-5472.can-07-6460
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Taguchi, Ayumu;Yanagisawa, Kiyoshi;Takahashi, Takashi
MicroRNAs(MiRNAs)是一类独特的非编码小RNA，通过与3‘端非翻译区的不完全碱基配对，在转录后抑制靶基因的表达。我们先前报道了miR-17-92 miRNA簇在13q31.3处的扩增和过表达，以及针对miR-17-5p和miR-20a的反义寡核苷酸治疗对miR-17-92的生长抑制，特别是在miR-17-92高表达的肺癌细胞系中。虽然这些发现清楚地表明miR-17-92在肺癌中过表达的重要作用，但到目前为止，只有几个miR-17-92簇的靶点被确定。在这项研究中，我们使用等压标记试剂iTRAQ，结合生物信息学靶标预测，通过全球表达谱分析确定缺氧诱导因子-1α是miR-17-92的新的直接靶标。这是第一个描述由miRNA对HIF-1α进行负调控的报告，这种负调控似乎没有中断HIF-1α对细胞对低氧适应的诱导。此外，c-myc的过度表达导致HIF-1α的下调和miR-17-92的诱导，后者先前被报道为转录激活活性，提示miR-17-92的诱导可能至少部分地在c-myc介导的HIF-1α的抑制中起作用。结合以前关于HIF-1α对c-myc功能负调控的报道，我们的发现表明可能存在涉及c-myc、miR-17-92和HIF-1α的复杂和微调的电路，该电路可能以细胞上下文依赖的方式在常氧条件下对癌细胞的增殖起作用。
MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs that posttranscriptionally repress expression of target genes through imperfect base pairing with the 3' untranslated region. We previously reported amplification and overexpression of the miR-17-92 miRNA cluster at 13q31.3 in lung cancers, as well as growth inhibition by treatment with antisense oligonucleotides against miR-17-5p and miR-20a, constituents of miR-17-92, specifically in miR-17-92-overexpressing lung cancer cell lines. Although these findings clearly suggested important roles of miR-17-92 overexpression in lung cancers, only a few targets for the miR-17-92 cluster have been identified thus far. In this study, we identified hypoxia-inducible factor (HIF)-1 alpha as a novel direct target for miR-17-92 through global expression profiling by mass spectrometric analysis using an isobaric tagging reagent, iTRAQ, combined with bioinformatic target prediction. This is the first report to describe negative regulation of HIF-1 alpha, by miRNA, which seemed to occur without disrupting the induction of HIF-1 alpha for cellular adaptation to hypoxia. In addition, overexpression of c-myc led to down-regulation of HIF-1 alpha and induction of miR-17-92, the latter of which was previously reported to be a transcriptional activation activity, suggesting that the induction of miR-17-92 may play a role at least in part in c-myc-mediated repression of HIF-1 alpha. Together with previous reports on the functional negative regulation of c-myc by HIF-1 alpha, our findings suggest the possible existence of an intricate and finely tuned circuit involving c-myc, miR-17-92, and HIF-1 alpha that may play a role in cancer cell proliferation under normoxia in a cellular context-dependent manner.