title: Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II.
abstract: 5-fluorouracil (5-FU)-based chemotherapy is widely used in the treatment of human hepatocellular carcinoma. However, despite impressive initial clinical responses, the majority of patients eventually develop resistance to 5-FU. The microRNA (miR)-125 family has been implicated in a variety of carcinomas as either a tumor suppressor or promoter. In the present study, the role of miR-125b in acquired 5-FU resistance in multiple human hepatocellular carcinoma cell lines was investigated using transfection of miR-125b. Compared with 5-FU?sensitive cells, 5?FU?resistant cells exhibited reduced expression levels of miR?125b. Furthermore, transfection of pre?miR-125b into liver cancer cells resulted in sensitization of 5-FU?resistant cells to 5-FU. In addition, the glucose uptake and lactate production in 5-FU?resistant liver cancer cells were demonstrated to be significantly increased compared with 5?FU?sensitive cells (P<0.05), indicating that targeting glycolytic pathways may overcome chemoresistance in human liver cancer cells. Notably, miR-125 was found to downregulate glucose metabolism by directly targeting hexokinase II. Since drug resistance is a common phenotype of malignant cancer cells, the finding that miR-125b expression levels are negatively correlated with 5-FU resistance in hepatocellular carcinoma cells is consistent with the reported functions of miR-125b. In conclusion, the present study identified miR-125b as a tumor suppressor-like microRNA, which exhibits great potential as a diagnostic and prognostic biomarker in hepatocellular carcinoma.
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Department of Digestive Internal Medicine, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Yao-Zhen
authors.initials: YZ
authors.lastname: Pan
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Sun
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D056945:Hep G2 Cells; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D006593:Hexokinase; D005947:Glucose; D005472:Fluorouracil