miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity
miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity
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DOI：
10.1038/cdd.2010.119
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发表时间：
2011-03-01
影响因子：
12.4
通讯作者：
Mari, B.
中科院分区：
文献类型：
--
作者：
Puissegur, M-P;Mazure, N. M.;Mari, B.
在鉴定出一组缺氧调节的 microRNA (miRNA) 后，最近的研究强调了 miR-210 及其转录因子缺氧诱导因子-1 (HIF-1) 转录调节的重要性。我们在此报告，miR-210 在非小细胞肺癌晚期过度表达。肺腺癌 A549 细胞中 miR-210 的表达引起与 caspase-3/7 活性诱导相关的细胞活力的改变。 miR-210 诱导线粒体膜电位丧失和异常线粒体表型的出现。过表达 miR-210 的细胞的表达谱揭示了一种特定的特征，其特征是与“细胞死亡”和“线粒体功能障碍”相关的转录物富集，包括电子传递链 (ETC) 复合物 I 和 II 的几个亚基。编码这些 ETC 成分之一 SDHD（琥珀酸脱氢酶复合物 (SDH) 的 D 亚基）的转录本已被验证为真正的 miR-210 靶标。此外，SDHD 敲低模拟了 miR-210 介导的线粒体改变。最后，SDHD 的 miR-210 依赖性靶向能够激活 HIF-1，这与之前将功能丧失性 SDH 突变与 HIF-1 激活联系起来的研究一致。因此，miR-210 可以通过靶向关键的 ETC 组成基因来调节线粒体功能，对细胞代谢、存活和 HIF-1 活性的调节产生重要影响。这些观察结果有助于解释有关 miR-210 表达及其在实体瘤中的推定功能的矛盾数据。细胞死亡与分化 (2011) 18, 465-478; doi：10.1038/cdd.2010.119； 2010 年 10 月 1 日在线发布
Following the identification of a set of hypoxia-regulated microRNAs (miRNAs), recent studies have highlighted the importance of miR-210 and of its transcriptional regulation by the transcription factor hypoxia-inducible factor-1 (HIF-1). We report here that miR-210 is overexpressed at late stages of non-small cell lung cancer. Expression of miR-210 in lung adenocarcinoma A549 cells caused an alteration of cell viability associated with induction of caspase-3/7 activity. miR-210 induced a loss of mitochondrial membrane potential and the apparition of an aberrant mitochondrial phenotype. The expression profiling of cells overexpressing miR-210 revealed a specific signature characterized by enrichment for transcripts related to 'cell death' and 'mitochondrial dysfunction', including several subunits of the electron transport chain (ETC) complexes I and II. The transcript coding for one of these ETC components, SDHD, subunit D of succinate dehydrogenase complex (SDH), was validated as a bona fide miR-210 target. Moreover, SDHD knockdown mimicked miR-210-mediated mitochondrial alterations. Finally, miR-210-dependent targeting of SDHD was able to activate HIF-1, in line with previous studies linking loss-of-function SDH mutations to HIF-1 activation. miR-210 can thus regulate mitochondrial function by targeting key ETC component genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data regarding miR-210 expression and its putative function in solid tumors. Cell Death and Differentiation (2011) 18, 465-478; doi:10.1038/cdd.2010.119; published online 1 October 2010