MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer
MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer
复制标题
MiR-199a-5p 与恶性肿瘤呈负相关，并通过靶向肝癌中的己糖激酶 2 来调节糖酵解和乳酸的产生
DOI：
10.1002/hep.27929
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发表时间：
2015-10-01
期刊：
影响因子：
13.5
通讯作者：
He, Xianghuo
中科院分区：
文献类型：
--
作者：
Guo, Weijie;Qiu, Zhaoping;He, Xianghuo
癌细胞具有独特的代谢表型，使其能够通过有氧糖酵解优先利用葡萄糖。这种现象被称为瓦尔堡效应。越来越多的证据表明，microRNAs（miRNAs），一类小的非编码调节RNA，与癌基因/肿瘤抑制因子相互作用，并诱导癌细胞中的这种代谢重编程。为了系统地研究miRNA在癌细胞中的代谢作用，我们在HeLa细胞中开发了功能获得性miRNA筛选。随后的研究表明，miR-199 a-5 p是葡萄糖代谢的抑制因子。此外，miR-199 a-5 p在人肝癌中常下调，其低表达水平与患者生存率低、肿瘤体积大、肿瘤分化状态差、肿瘤淋巴结转移分期高以及存在癌栓相关。MicroRNA-199 a-5 p直接靶向己糖激酶2（HK 2）的3-非翻译区，HK 2是一种催化糖酵解不可逆第一步的酶，从而抑制葡萄糖消耗、乳酸盐产生、细胞葡萄糖-6-磷酸和三磷酸腺苷水平、细胞增殖和肝癌细胞的肿瘤发生。此外，HK 2在肝癌组织中经常上调，并与患者预后不良相关。低氧诱导因子-1在低氧条件下的上调抑制了miR-199 a-5 p的表达并促进糖酵解，而重新引入miR-199 a-5 p则干扰了HK 2的表达，从而消除了低氧促进的糖酵解。结论：miR-199 a-5 p/HK 2可重新编程肝癌细胞的代谢过程，并为肝癌患者提供潜在的预后预测因子。（肝病学2015;62：1132-1144）
Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the Warburg effect. Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain-of-function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR-199a-5p acts as a suppressor for glucose metabolism. Furthermore, miR-199a-5p is often down-regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumor-node-metastasis stage and the presence of tumor thrombus of patients. MicroRNA-199a-5p directly targets the 3-untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose-6-phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up-regulated in liver cancer tissues and associated with poor patient outcomes. The up-regulation of hypoxia-inducible factor-1 under hypoxic conditions suppresses the expression of miR-199a-5p and promotes glycolysis, whereas reintroduction of miR-199a-5p interferes with the expression of HK2, abrogating hypoxia-enhanced glycolysis. Conclusion: miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients. (Hepatology 2015;62:1132-1144)