Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer.
Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer.
复制标题
DOI：
10.1186/s12943-018-0851-8
复制
发表时间：
2018-07-16
期刊：
影响因子：
37.3
通讯作者：
Alahari SK
中科院分区：
文献类型：
--
作者：
Eastlack SC;Dong S;Ivan C;Alahari SK
由于 microRNA 功能障碍导致正常基因调控的破坏是癌症发病机制中的常见事件。 MicroRNA-27b 是致癌 miRNA 的一个例子，它在乳腺癌中经常上调。人们发现 MicroRNA 可以解除肿瘤代谢的调节，这通常表现为细胞葡萄糖摄取增加，同时糖酵解通量增加，随后糖酵解丙酮酸优先转化为乳酸（这种现象称为瓦伯格效应）。丙酮酸脱氢酶是一种将糖酵解与下游氧化代谢联系起来的酶复合物，是代谢调节发生的关键位置； PDHX 是该复合物的关键结构成分，对其功能至关重要。我们试图通过鉴定 miR-27b 控制下的新转录本来表征 miR-27b 在乳腺癌中的作用。我们首先利用荧光素酶、RNA 和蛋白质检测将 PDHX 确立为 miR-27b 的新靶标。然后，我们使用几种代谢物检测试剂盒测试了 miR-27b 是否可以改变代谢，并进行了海马分析。我们还研究了新陈代谢的改变如何影响细胞增殖。最后，我们证实了我们的研究结果在人类乳腺肿瘤样本中的相关性。我们的数据表明丙酮酸脱氢酶蛋白 X 是乳腺癌中 miR-27b 的可靠靶标。从机制上讲，通过抑制 PDHX，miR-27b 改变了丙酮酸、乳酸和柠檬酸的水平，并减少线粒体氧化并促进细胞外酸化。这些变化与细胞增殖能力的增强相对应。在人类乳腺肿瘤样本中，PDHX 表达不足，低水平的 PDHX 与患者生存率降低相关。 MicroRNA-27b 以 PDHX 为目标，导致代谢结构发生改变，更适合促进生物合成过程和细胞增殖，从而促进乳腺癌进展。本文的在线版本 (10.1186/s12943-018-0851-8) 包含补充材料，可供授权用户使用。
The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function. We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples. Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival. MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression. The online version of this article (10.1186/s12943-018-0851-8) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
--
作者：
De Preter G;Neveu MA;Danhier P;Brisson L;Payen VL;Porporato PE;Jordan BF;Sonveaux P;Gallez B
通讯作者：
Gallez B
影响因子：
4.3
作者：
Baenke F;Peck B;Miess H;Schulze A
通讯作者：
Schulze A
DOI：
10.1093/jnci/djr350
发表时间：
2011-10-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Baranwal, Somesh;Wang, Yanfang;Alahari, Suresh K.
通讯作者：
Alahari, Suresh K.
影响因子：
64.5
作者：
LEE, RC;FEINBAUM, RL;AMBROS, V
通讯作者：
AMBROS, V