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)-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.
Tomimaru
Y
Y
Department of Surgery, Graduate School of Medicine, Osaka University, Suita, 2-2 Yamadaoka E-2, Osaka 565-0871, Japan.
Eguchi
H
H
Nagano
H
H
Wada
H
H
Tomokuni
A
A
Kobayashi
S
S
Marubashi
S
S
Takeda
Y
Y
Tanemura
M
M
Umeshita
K
K
Doki
Y
Y
Mori
M
M
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014162:Transfection
D000970:Antineoplastic Agents; D017931:DNA Primers; D016898:Interferon-alpha; D035683:MicroRNAs; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D005472:Fluorouracil