Decreased expression of mitochondrial miR-5787 contributes to chemoresistance by reprogramming glucose metabolism and inhibiting MT-CO3 translation
Decreased expression of mitochondrial miR-5787 contributes to chemoresistance by reprogramming glucose metabolism and inhibiting MT-CO3 translation
复制标题
线粒体 miR-5787 表达减少通过重新编程葡萄糖代谢和抑制 MT-CO3 翻译而导致化疗耐药
DOI：
10.7150/thno.37556
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Fan, Song
中科院分区：
文献类型：
--
作者：
Chen, Weixiong;Wang, Peng;Fan, Song
最近在线粒体中发现了微小RNA（miRNAs），并将其命名为“mitomiRs”，但它们的功能仍然难以捉摸。本研究旨在探讨舌鳞状细胞癌（tongue squamous cell carcinoma，TSCC）中mitomiRs的存在及其功能。在化学抗性细胞中的mitomiRs的表达降低的特征在于。结果：差异表达基因芯片分析显示，在Cal 27-re细胞中，mitomiR-5787表达下调。我们敲低了亲代细胞中的mitomiR-5787，并上调了其在顺铂耐药细胞中的表达。TSCC细胞对顺铂的敏感性受miR-5787调节。葡萄糖代谢测定表明，miR-5787的表达减少改变了葡萄糖代谢的平衡，使其从氧化磷酸化转变为有氧糖酵解。BALB/c-nu小鼠的异种移植实验进一步验证了体外结果。miR-5787的表达减少通过抑制线粒体细胞色素c氧化酶亚基3（MT-CO 3）的翻译而导致TSCC细胞的化学抗性。结论：线粒体miR-5787可调控TSCC细胞对顺铂的耐药性，影响细胞的氧化磷酸化和有氧糖酵解。下调miR-5787可抑制MT-CO 3的翻译，从而调节TSCC的顺铂耐药。线粒体miR-5787和MT-CO 3可作为顺铂化疗耐药的预测性生物标志物或治疗靶点。
MicroRNAs (miRNAs) have been recently found in the mitochondria, and were named "mitomiRs", but their function has remained elusive. Here, we aimed to assess the presence and function(s) of mitomiRs in tongue squamous cell carcinoma (TSCC).Methods: miRNA microarray was performed in paired TSCC cell lines, Cal27 and its chemoresistant counterpart, Cal27-re. Decreased expression of mitomiRs in chemoresistant cells was characterized. The functions of mitomiRs were investigated by a series of in vitro and in vivo experiments.Results: Differential microarray analysis identified downregulation of mitomiR-5787 in Cal27-re cells. We knocked down mitomiR-5787 in parental cells and upregulated its expression in cisplatin-resistant cells. The sensitivity of TSCC cells to cisplatin was regulated by miR-5787. The glucose metabolism assay suggested that reduced expression of miR-5787 changed the balance of glucose metabolism by shifting it from oxidative phosphorylation to aerobic glycolysis. Xenograft experiments in BALB/c-nu mice further verified the in vitro results. Reduced expression of miR-5787 contributes to chemoresistance in TSCC cells by inhibiting the translation of mitochondrial cytochrome c oxidase subunit 3 (MT-CO3). The prognostic analysis of 126 TSCC patients showed that the patients with low expression of miR-5787 and/or MT-CO3 had poor cisplatin sensitivity and prognosis.Conclusions: Mitochondrial miR-5787 could regulate cisplatin resistance of TSCC cells and affect oxidative phosphorylation and aerobic glycolysis. Downregulation of miR-5787 inhibited the translation of MT-CO3 to regulate cisplatin resistance of TSCC. Mitochondrial miR-5787 and MT-CO3 can be used as predictive biomarkers or therapeutic targets for cisplatin chemotherapy resistance.