title: Interferon-gamma sensitizes hepatitis B virus-expressing hepatocarcinoma cells to 5-fluorouracil through inhibition of hepatitis B virus-mediated nuclear factor-kappaB activation.
abstract: Nuclear factor (NF)-kappaB is important for immune responses and cell survival; however, abnormal activation of NF-kappaB is linked with many types of diseases, including hepatocellular carcinoma (HCC). Our previous report indicated that hepatitis B virus (HBV) induces NF-kappaB activation through NF-kappaB-inducing kinase (NIK), and this can be blocked specifically by interferon (IFN)-gamma. In the present study, we report that HBV expression in HCC cell lines induces drug resistance against 5-fluorouracil (5-FU). This drug resistance was abolished by inhibition of NF-kappaB activation through small interfering RNA-mediated NIK 'knockdown' and IFN-gamma treatment. In addition to the reduced NF-kappaB activation and drug resistance, the upregulated growth arrest- and DNA damage-inducible protein 45beta (Gadd45beta) in HBV-expressing HCC cell lines was downregulated by the small interfering RNA-mediated NIK knockdown and IFN-gamma treatment. The overexpression of Gadd45beta in HCC cell lines also induces drug resistance against 5-FU. Based on our data, we suggest that IFN-gamma treatment might be helpful for chemotherapy in HBV-integrated HCC through inhibition of the NIK-mediated NF-kappaB activation and downregulation of the NF-kappaB target gene Gadd45beta.
authors: School of Biological Sciences, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, Korea.
authors: Chan
authors: C
authors: Chung
authors: Sung Gyoo
authors: SG
authors: Park
authors: Young Min
authors: YM
authors: Park
authors: Jae-Won
authors: JW
authors: Joh
authors: Guhung
authors: G
authors: Jung
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000821:virology*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000627:therapeutic use*; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000821:virology*; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D016899:Interferon-beta; D008156:Luciferases; D005472:Fluorouracil
references: Blood. 2003 Nov 1;102(9):3270-9
references: 12855571
references: Science. 1965 Jul 16;149(3681):310-1
references: 17533668
references: J Biol Chem. 2002 Mar 8;277(10):7920-8
references: 11773061
references: Oncogene. 1991 Jan;6(1):165-7
references: 1899477
references: Semin Cancer Biol. 2003 Apr;13(2):107-14
references: 12654254
references: Trends Cell Biol. 2001 Nov;11(11):S22-6
references: 11684438
references: Proc Natl Acad Sci U S A. 1987 Feb;84(4):1005-9
references: 3029758
references: BMJ. 1999 May 1;318(7192):1213
references: 10221961
references: Cancer. 1988 May 15;61(10):1942-56
references: 2834034
references: Cancer Lett. 2005 Nov 18;229(2):271-81
references: 16135400
references: Oncogene. 1996 Jun 20;12(12):2579-94
references: 8700517
references: Cell. 2004 Aug 6;118(3):285-96
references: 15294155
references: J Biol Chem. 2004 May 28;279(22):23477-85
references: 15026414
references: Clin Cancer Res. 2001 Oct;7(10):3269-75
references: 11595724
references: Science. 1994 Nov 25;266(5189):1376-80
references: 7973727
references: World J Gastroenterol. 2006 Aug 21;12(31):4986-95
references: 16937494
references: Oncogene. 1995 Nov 2;11(9):1675-83
references: 7478594
references: Arch Biochem Biophys. 2000 Aug 1;380(1):108-16
references: 10900139
references: Cell. 1998 Nov 13;95(4):521-30
references: 9827804
references: Trends Immunol. 2004 Jun;25(6):280-8
references: 15145317
references: Cancer Treat Rev. 1988 Mar;15(1):1-31
references: 2834053
references: Cancer Res. 2006 Aug 1;66(15):7598-605
references: 16885359
references: J Cell Physiol. 1999 Nov;181(2):188-202
references: 10497299
references: Cancer Res. 2000 Oct 1;60(19):5451-5
references: 11034087
references: FASEB J. 2001 Nov;15(13):2551-3
references: 11641261
references: Oncogene. 2002 Sep 19;21(42):6510-9
references: 12226754
references: Nat Rev Cancer. 2005 Apr;5(4):297-309
references: 15803156
references: Oncogene. 2006 Aug 7;25(34):4798-811
references: 16892092
references: Oncogene. 1999 May 6;18(18):2892-900
references: 10362260
references: J Biol Chem. 2000 Jun 2;275(22):16602-8
references: 10747892
references: Int J Clin Pharmacol Ther. 2002 Aug;40(8):336-47
references: 12467302
references: J Biol Chem. 2003 Oct 10;278(41):39851-7
references: 12869561
references: Gastroenterology. 2005 Jun;128(7):2042-53
references: 15940636
references: J Virol. 2005 Jul;79(14):8948-59
references: 15994789
references: J Biol Chem. 2006 Jan 27;281(4):2162-9
references: 16280329
references: Eur J Cancer. 2004 Jul;40(10):1474-84
references: 15196530
references: Nat Med. 1999 Apr;5(4):412-7
references: 10202930
references: J Natl Cancer Inst. 1992 Feb 19;84(4):262-4
references: 1346405
references: Lancet. 1978 May 13;1(8072):1006-9
references: 76932
references: Oncogene. 2003 Dec 8;22(56):8961-82
references: 14663476
references: Oncogene. 2006 Sep 7;25(40):5537-46
references: 16732331
references: Nature. 2001 Nov 15;414(6861):308-13
references: 11713530
references: J Biol Chem. 2002 Mar 29;277(13):10842-51
references: 11801607
references: J Virol. 2007 Jan;81(1):272-9
references: 17035315
references: EMBO J. 2003 Jun 2;22(11):2552-60
references: 12773372
references: Oncogene. 1999 Aug 12;18(32):4554-63
references: 10467400
references: Semin Cancer Biol. 2000 Jun;10(3):211-31
references: 10936070
references: Nat Rev Cancer. 2003 May;3(5):330-8
references: 12724731
references: Cell. 2002 Apr;109 Suppl:S81-96
references: 11983155
references: J Virol. 2001 Jan;75(1):215-25
references: 11119591
references: Clin Cancer Res. 1999 Jan;5(1):119-27
references: 9918209
references: Cancer Cell. 2002 Oct;2(4):335-46
references: 12398897
references: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3706-11
references: 10097101
references: Cancer Lett. 2002 Oct 8;184(1):97-104
references: 12104053
references: Cancer Res. 2003 Jan 1;63(1):107-10
references: 12517785
references: FEBS Lett. 2006 Feb 6;580(3):822-30
references: 16413545
references: J Clin Invest. 2001 Jan;107(2):135-42
references: 11160126
references: Oncogene. 2003 May 22;22(21):3243-51
references: 12761494
references: Cancer Res. 2004 Nov 15;64(22):8167-76
references: 15548681
references: Oncogene. 2001 Feb 15;20(7):859-68
references: 11314019
references: Nature. 2004 Sep 23;431(7007):461-6
references: 15329734
references: J Biol Chem. 2001 Jul 6;276(27):25073-7
references: 11340079
references: J Hepatol. 2001 Sep;35(3):421-30
references: 11592607
references: Cancer. 1988 Aug 1;62(3):479-83
references: 2839280
references: Oncogene. 2000 Aug 24;19(36):4159-69
references: 10962577
references: Hepatology. 2002 Dec;36(6):1498-508
references: 12447876
references: J Gastroenterol Hepatol. 1997 Aug;12(8):569-75
references: 9304508