Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II

Jiang,Jian-Xin; Gao,Shan; Pan,Yao-Zhen; Yu,Chao; Sun,Cheng-Yi

doi:10.3892/mmr.2014.2271

Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II

Authors:
- Jian-Xin Jiang
- Shan Gao
- Yao-Zhen Pan
- Chao Yu
- Cheng-Yi Sun
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Affiliations: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China, Department of Digestive Internal Medicine, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
Published online on: May 26, 2014 https://doi.org/10.3892/mmr.2014.2271
Pages: 995-1002

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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.

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