MiR‐199a‐5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer

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. 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)