MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells

BACKGROUND: We reported recently the clinical efficiency of interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC). However, prediction of the response to the combination therapy remains unsatisfactory. The aim of this study was to investigate the anti-tumour effects of microRNA (miR)-21 on the sensitivity of HCC cells to IFN-alpha/5-FU and whether miR-21 can be used as a predictor of the response to such therapy in HCC. METHODS: Changes in the sensitivity of HCC cells (PLC/PRF/5 and HepG2) to IFN-alpha/5-FU were examined after transfection with pre-miR-21 or anti-miR-21. The correlation between miR-21 expression level, evaluated by qRT-PCR, and response to the therapy was also investigated in clinical HCC specimens. RESULTS: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Annexin V assay showed that the percentage of apoptotic cells was significantly lower in cells transfected with pre-miR-21 than control cells. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4. miR-21 expression in clinical HCC specimens was significantly associated with the clinical response to the IFN-alpha/5-FU combination therapy and survival rate. CONCLUSIONS: The miR-21 in HCC cell lines and clinical HCC samples is a significant modulator of the anti-tumour effect of IFN-alpha and 5-FU. This suggests that miR-21 is a potentially suitable marker for the prediction of the clinical response to the IFN-alpha/5-FU combination therapy. British Journal of Cancer (2010) 103, 1617-1626. doi:10.1038/sj.bjc.6605958 www.bjcancer.com Published online 26 October 2010 (C) 2010 Cancer Research UK