Shanghai Medical College, Fudan University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Hepatology. 2015 Oct;62(4):1132-44. doi: 10.1002/hep.27929. Epub 2015 Jul 4.
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-1α 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.
miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients.
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“沃伯格效应”。越来越多的证据表明，microRNAs（miRNAs）是一类小的非编码调节 RNA，与癌基因/肿瘤抑制因子相互作用，并诱导癌细胞发生这种代谢重编程。为了系统研究 miRNAs 在癌细胞中的代谢作用，我们在 HeLa 细胞中开发了一种 miRNA 功能获得筛选。对鉴定出的 miRNAs 的后续研究表明，miR-199a-5p 作为葡萄糖代谢的抑制剂发挥作用。此外，miR-199a-5p 在人肝癌中常被下调，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肿瘤栓子相关。miR-199a-5p 可直接靶向己糖激酶 2（HK2）的 3'-非翻译区，该酶催化糖酵解的不可逆第一步，从而抑制葡萄糖消耗、乳酸生成、细胞内葡萄糖-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，HK2 在肝癌组织中常被上调，并与患者预后不良相关。在缺氧条件下，缺氧诱导因子-1α 的上调抑制 miR-199a-5p 的表达并促进糖酵解，而 miR-199a-5p 的再引入干扰 HK2 的表达，阻断缺氧增强的糖酵解。
miR-199a-5p/HK2 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指标。
