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

Abstract

Background:We reported recently the clinical efficiency of interferon (IFN)-α/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-α/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-α/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-α/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-α/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-α/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-α and 5-FU. This suggests that miR-21 is a potentially suitable marker for the prediction of the clinical response to the IFN-α/5-FU combination therapy.

Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA

“…Previous measurements of miRNAs in liver samples revealed that let-7a, miR-16, miR-20, miR-21, and miR-22 were present at 700, 3 890, 130, 4 450, and 310 copies per cell, respectively [43], while miR-181a was expressed at 810 copies per cell in DP thymocytes [44] and miR-223 and miR-451 were 828 and 1 972 copies per cell in CD34(+)/CD133(−) cells [45]. It has been widely demonstrated that miRNAs expressed at these concentrations are biologically active [46][47][48][49]. We calculated the amount of MIR168a that was detected in 1 mg of total liver RNA.…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…Another miRNA that has been shown to be involved in chemoresistance is miR-21. miR-21-transfected HCC cells are resistant to 5-fluorouracil/interferon-α [115] , which suggests that anti-miR-21 may increase the chemosensitivity of cancer cells. Indeed, anti-miR-21 improves the cytotoxicity induced by 5-FU in glioblastoma cells [116] .…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…These mechanisms lead to the stimulation of cell proliferation promoting migration and invasion. Tomimaru et al (2010) have demonstrated that miR-21 has an effect in the modulation of the response to IFN-␣/5-FU favoring the clinical response and survival. This miRNA is the first to be studied as a therapeutic tool and other two studies (Connolly et al, 2008;Zhu et al, 2011) have shown that the transfection of tumor cells with antisense oligonucleotides specific for mir-21 leads to a reduction of the cell growth and survival.…”