title: 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-alpha 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-alpha were examined in HCC cells after genetic manipulation of IGFBP7 expression. The correlation between immunohistochemically determined IGFBP7 expression and the response to IFN-alpha/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-alpha, compared with PLC-P. Parental PLC/PRF/5 cells transfected with short hairpin RNA against IGFBP7 showed a significant resistance to IFN-alpha 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-alpha. In resected specimens, IGFBP7 expression significantly correlated with the response to IFN-alpha/5-FU therapy.
  
  
  CONCLUSIONS
  IGFBP7 could be a useful predictor of the response to IFN-based therapy in advanced HCC.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomimaru
authors.forename: H
authors.initials: H
authors.lastname: Eguchi
authors.forename: H
authors.initials: H
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Noda
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Marubashi
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: M
authors.initials: M
authors.lastname: Tanemura
authors.forename: K
authors.initials: K
authors.lastname: Umeshita
authors.forename: Y
authors.initials: Y
authors.lastname: Doki
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: H
authors.initials: H
authors.lastname: Nagano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000627:therapeutic use; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018969:Insulin-Like Growth Factor Binding Proteins; D016898:Interferon-alpha; C102529:insulin-like growth factor binding protein-related protein 1; D005472:Fluorouracil
references.citation: J Hepatol. 1999 Apr;30(4):660-8
references.pmid: 10207808
references.citation: Cancer. 2006 May 1;106(9):1990-7
references.pmid: 16565970
references.citation: Clin Cancer Res. 2000 Jul;6(7):2881-90
references.pmid: 10914738
references.citation: Cancer. 2002 Jan 15;94(2):435-42
references.pmid: 11900229
references.citation: J Hepatol. 2007 Jan;46(1):77-88
references.pmid: 17045692
references.citation: Anticancer Res. 2007 Sep-Oct;27(5B):3513-8
references.pmid: 17972510
references.citation: Genes Dev. 2005 Dec 15;19(24):2953-68
references.pmid: 16319195
references.citation: Hepatogastroenterology. 2007 Jan-Feb;54(73):172-9
references.pmid: 17419255
references.citation: BMC Cancer. 2009 Oct 12;9:361
references.pmid: 19821965
references.citation: Br J Cancer. 2005 Sep 5;93(5):557-64
references.pmid: 16106266
references.citation: Cancer Res. 2003 Nov 15;63(22):7717-23
references.pmid: 14633696
references.citation: J Clin Oncol. 2003 Feb 1;21(3):421-7
references.pmid: 12560429
references.citation: Hepatogastroenterology. 1996 May-Jun;43(9):637-43
references.pmid: 8799408
references.citation: Clin Cancer Res. 1999 Dec;5(12):4005-12
references.pmid: 10632332
references.citation: Oncogene. 1998 May 14;16(19):2459-67
references.pmid: 9627112
references.citation: Clin Cancer Res. 1999 Jul;5(7):1676-81
references.pmid: 10430068
references.citation: Oncol Rep. 2007 Oct;18(4):801-9
references.pmid: 17786339
references.citation: Br J Cancer. 2009 May 19;100(10):1647-58
references.pmid: 19401692
references.citation: Am J Clin Oncol. 1982 Dec;5(6):649-55
references.pmid: 7165009
references.citation: Cancer Sci. 2007 Jul;98(7):1055-63
references.pmid: 17465992
references.citation: Int J Oncol. 2000 Jul;17(1):83-8
references.pmid: 10853022
references.citation: Cancer. 2000 May 1;88(9):1986-91
references.pmid: 10813709
references.citation: Cancer. 1997 Jun 1;79(11):2087-94
references.pmid: 9179054
references.citation: Hepatol Res. 2007 Jan;37(1):77-83
references.pmid: 17300701
references.citation: Cancer. 2007 Dec 1;110(11):2493-501
references.pmid: 17941012
references.citation: Clin Cancer Res. 2004 Dec 1;10(23):7884-95
references.pmid: 15585621
references.citation: Oncology. 1998 Jan-Feb;55(1):39-47
references.pmid: 9428374
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1277-86
references.pmid: 15709199
references.citation: Hepatogastroenterology. 1999 May-Jun;46(27):1862-9
references.pmid: 10430360
references.citation: Breast Cancer Res Treat. 1998 Feb;47(3):283-93
references.pmid: 9516082
references.citation: Cell. 2008 Feb 8;132(3):363-74
references.pmid: 18267069
references.citation: Cytometry A. 2005 Nov;68(1):28-35
references.pmid: 16184612
references.citation: Hepatol Res. 2007 Sep;37 Suppl 2:S238-50
references.pmid: 17877489
references.citation: Radiology. 1997 Sep;204(3):787-90
references.pmid: 9280260
references.citation: Oncogene. 2001 Jun 14;20(27):3497-505
references.pmid: 11429696
references.citation: Cancer Biol Ther. 2008 Dec;7(12):1896-900
references.pmid: 18981723