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

• Published in: British journal of cancer Vol. 103; no. 10; pp. 1617 - 1626
• Main Authors: TOMIMARU, Y, EGUCHI, H, DOKI, Y, MORI, M, NAGANO, H, WADA, H, TOMOKUNI, A, KOBAYASHI, S, MARUBASHI, S, TAKEDA, Y, TANEMURA, M, UMESHITA, K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 09.11.2010
• Subjects: 5-Fluorouracil; Antineoplastic Agents - antagonists & inhibitors; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cell Division - drug effects; DNA Primers; Drug Evaluation, Preclinical; Drug Resistance; Drug Resistance, Neoplasm; Fluorouracil - antagonists & inhibitors; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunohistochemistry; Interferon-alpha - antagonists & inhibitors; Interferon-alpha - therapeutic use; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; MicroRNAs - genetics; MicroRNAs - pharmacology; Molecular Diagnostics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Neoplasm - genetics; Survival Rate; Transfection; Tumors; Antineoplastic agent; RNA interference; Alpha interferon; Phosphoric monoester hydrolases; Hepatic disease; Hepatocellular carcinoma; Homology; Esterases; 5-fluorouracil (5-FU); Liver cancer; Cancerology; PTEN Gene; miR-21; programmed cell death 4 (PDCD4); Fluorouracil; Tumor suppressor gene; interferon-α (IFN-α); Enzyme; Fluoropyrimidine derivatives; Transferases; Micro RNA; Enzyme inhibitor; hepatocellular carcinoma (HCC); Malignant tumor; Thymidylate synthase; Resistance; Gene silencing; Antimetabolic; Methyltransferases; Cell death; Pyrimidine derivatives; Hydrolases; Digestive diseases; phosphatase and tensin homologue (PTEN); Cancer; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605958

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. 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. 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. 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.