Insulin-like growth factor-binding protein 7 alters the sensitivity to interferon-based anticancer therapy in hepatocellular carcinoma cells

• Published in: British journal of cancer Vol. 102; no. 10; pp. 1483 - 1490
• Main Authors: Tomimaru, Y, Eguchi, H, Wada, H, Noda, T, Murakami, M, Kobayashi, S, Marubashi, S, Takeda, Y, Tanemura, M, Umeshita, K, Doki, Y, Mori, M, Nagano, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2010; Nature Publishing Group
• Subjects: 692/53/2422; 692/699/67/1059/99; 692/699/67/1504/1610; Antibodies; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; Cell Line, Tumor; Cloning; Drug Resistance; Drug Resistance, Neoplasm - genetics; Efficiency; Epidemiology; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Gene Expression Profiling; Humans; Immunohistochemistry; Immunoprecipitation; Insulin; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - metabolism; Insulin-like growth factors; Interferon; Interferon-alpha - pharmacology; Kaplan-Meier Estimate; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Liver cancer; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical research; Medical sciences; Molecular Medicine; Oligonucleotide Array Sequence Analysis; Oncology; Prognosis; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Translational Therapeutics; Tumors; United States > US; Japan; 5-fluorouracil; interferon; hepatocellular carcinoma; insulin-like growth factor-binding protein 7 (IGFBP7); Antineoplastic agent; Cell therapy; interferon-α; Alpha interferon; Hepatic disease; Hepatocellular carcinoma; Insulin like growth factor binding protein; Liver cancer; Cancerology; Fluorouracil; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; Malignant tumor; Thymidylate synthase; Sensitivity; Treatment; Antimetabolic; Methyltransferases; Pyrimidine derivatives; Digestive diseases; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605669

Background: A striking efficiency of interferon (IFN)-based anticancer therapy for advanced hepatocellular carcinoma (HCC) has been reported. Because its clinical efficiency greatly depends on each patient's local response, prediction of local response is crucial. Methods: Continuous exposure of IFN- α to parental PLC/PRF/5 cells (PLC-P) and a limiting dilution method resulted in the establishment of IFN-resistant cell clones (PLC-Rs). Microarray analyses of PLC-P and PLC-Rs identified insulin-like growth factor-binding protein 7 (IGFBP7) as one of the most significantly downregulated genes in PLC-Rs. Changes in anticancer effects of IFN- α were examined in HCC cells after genetic manipulation of IGFBP7 expression. The correlation between immunohistochemically determined IGFBP7 expression and the response to IFN- α /5-fluorouracil (5-FU) therapy was investigated in surgically resected HCC specimens. Results: PLC-R cells showed a remarkable downregulation of IGFBP7 and resistance to IFN- α , compared with PLC-P. Parental PLC/PRF/5 cells transfected with short hairpin RNA against IGFBP7 showed a significant resistance to IFN- α relative to control cells (IC 50 fold increase=14.38 times). Insulin-like growth factor-binding protein 7 transfection into PLC-R restored sensitivity to IFN- α . In resected specimens, IGFBP7 expression significantly correlated with the response to IFN- α /5-FU therapy. Conclusion: IGFBP7 could be a useful predictor of the response to IFN-based therapy in advanced HCC.