title: MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer.
abstract: 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.
  
  
  CONCLUSIONS
  miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients.
authors.affiliation: 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.
authors.forename: Weijie
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical College, Guilin, Guangxi, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Tan
authors.affiliation: Qidong Liver Cancer Institute, Qidong, Jiangsu, China.
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhiao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xianghuo
authors.initials: X
authors.lastname: He
mesh_terms: D005260:Female; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D014407:Tumor Cells, Cultured
chemical_list: D035683:MicroRNAs; C531408:mirn199 microRNA, human; D019344:Lactic Acid; D006593:Hexokinase