title: The up-regulation of type I interferon receptor gene plays a key role in hepatocellular carcinoma cells in the synergistic antiproliferative effect by 5-fluorouracil and interferon-alpha.
abstract: Combination therapy with interferon (IFN)-alpha and 5-fluorouracil (5-FU) has been reported to show an improved therapeutic efficacy in patients with advanced hepatocellular carcinoma (HCC) but the mechanism behind this has not been completely elucidated. We examined the molecular events underlying the antiproliferative effects of IFN-alpha and 5-FU in combination using six human HCC cell lines. When the antiproliferative effects of administering IFN-alpha and 5-FU together were analyzed using isobolograms, we found that the cell lines could be divided into two groups: the S-group containing three cell lines, which showed synergistic effects, and the A-group, containing the remaining three cell lines, which showed additive effects. Real-time RT-PCR and Western blot analyses revealed that the expression levels of type I IFN receptor subunits, IFNAR1 and IFNAR2, were specifically up-regulated by 5-FU in all three cell lines of the S-group with the exception of IFNAR2 in one cell line, but not in those of the A-group. IFN-alpha modulated the protein expression levels of six enzymes regulating sensitivity to 5-FU, but none of them were down- or up-regulated in the same way in all members of the S- or A-group. In conclusion, the 5-FU-induced modulation of IFN receptor expression could play a pivotal role in the therapeutic efficacy of IFN-alpha combined with 5-FU. Measuring the expression levels of IFN receptors, and their ability to be up-regulated, may be a promising method for selecting HCC patients for this type of combination therapy.
authors.affiliation: Station-II for Collaborative Research, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. oh9906ie@qa2.so-net.ne.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Oie
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Terada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kojiro
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hirano
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta; D005472:Fluorouracil