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

Y. Tomimaru, H. Eguchi, H. Wada, T. Noda, M. Murakami, S. Kobayashi, S. Marubashi, Y. Takeda, M. Tanemura, K. Umeshita, Y. Doki, M. Mori, H. Nagano

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Abstract

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 increase14.38 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.

Original languageEnglish
Pages (from-to)1483-1490
Number of pages8
JournalBritish journal of cancer
Volume102
Issue number10
DOIs
Publication statusPublished - May 1 2010

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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