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

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-a 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-a were examined in HCC cells after genetic manipulation of IGFBP7 expression. The correlation between immunohistochemically determined IGFBP7 expression and the response to IFN-a/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-a, compared with PLC-P. Parental PLC/ PRF/5 cells transfected with short hairpin RNA against IGFBP7 showed a significant resistance to IFN-a relative to control cells (IC 50 fold increase ¼ 14.38 times). Insulin-like growth factor-binding protein 7 transfection into PLC-R restored sensitivity to IFN-a. In resected specimens, IGFBP7 expression significantly correlated with the response to IFN-a/5-FU therapy. CONCLUSION: IGFBP7 could be a useful predictor of the response to IFN-based therapy in advanced HCC.

Type I and II IFNs Inhibit Merkel Cell Carcinoma via Modulation of the Merkel Cell Polyomavirus T Antigens

“…In general, the antiviral activity of PML and PML nuclear bodies are well established (21,(36)(37)(38) (44) or epigenetic silencing of genes involved in IFN signaling (45,46). Another report showed the suppression of insulin-like growth factor-binding protein 7 (IGFBP7) in IFN-a resistant hepatocellular carcinoma (HCC) cells (47). However, the crucial mechanism remains unknown.…”

Low expression of insulin-like growth factor binding protein 7 associated with poor prognosis in human glioma

“…30 Others have shown that short hairpin RNA directed against IGFBP7 increased resistance to interferon-a/5-fluorouracil treatment, and IGFBP7 transfection restored treatment sensitivity in HCC. 31 Intravenous recombinant IGFBP7 treatment has shown good tumour-suppressive effects in mouse models of several cancers, including glioblastoma. 28,32 The potential anticancer effects of IGFBP7 in glioma therefore warrant further investigation.…”

Insulin-Like-Growth Factor-Binding-Protein 7: An Antagonist to Breast Cancer

“…Parental PLC/PRF/5 cells transfected with short hairpin RNA for IGFBP7 showed IFN- resistance. IGFBP7 transfection into IFN-resistant HCC cells restored IFN sensitivity [106]. These results suggested that IGFBP7 could be a novel marker to predict clinical outcome to IFN-/5-FU therapy.…”

“…A strong antitumor activity against HCC has been demonstrated for interferon (IFN)-based combination therapy (IFN-/ 5-FU therapy) [106][107][108][109][110][111][112][113][114][115][116]. However continuous exposure to IFN- can result in IFN-resistant HCC cells.…”