Abstract: AIM: To investigate the role of ribonucleotide reductase M2 (RRM2) in 5-fluorouracil (5-FU) resistance of HCC cells and to develop potential strategies to enhance the sensitivity of HCC cells to 5-FU.  METHODS: The expression of RRM2 was examined by Western blot in BEL/5-FU cells and BEL7402 cells. The expression of RRM2 was down-regulated through RNA interference (RNAi) technology and the activity of RRM2 was inhibited by the RRM2 inhibitor 3-AP. The cell proliferation ability was detected by CCK-8 assay and colony formation assay, and the apoptosis was analyzed by Confocal high-content system. RESULTS: The expression level of RRM2 was increased by 2.5-fold in BEL/5-FU cells compared with BEL7402 cells. Compared with control siRNA, the half maximum inhibitory concentration IC50 of 5-FU in BEL/5-FU cells was decreased by about 50% via RRM2 down-regulation and the cell colony ability was significantly weakened in the treatment of 5-FU. The 5-FU IC50 of BEL/5-FU cells treated with 3-AP was decreased by about 40%, and the cell colony ability was significantly weakened and cell apoptosis was enhanced. CONCLUSION: RRM2 is related to the drug resistance of HCC cells to 5-FU. This study reverses the drug resistance of HCC cells to 5-FU by inhibiting the activity of RRM2, providing a new target and a new idea for improving the efficacy of 5-FU chemotherapy for HCC.

Key words: hepatocellular carcinoma, ribonucleotide reductase M2, resistance, 3-AP(Triapine), 5-fluorouracil