title: Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma.
abstract: Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). However, some IFNAR2-positive patients show no response to the therapy. This result suggests the possibility of other factors, which would be responsible for resistance to IFN-alpha/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-alpha/5-FU therapy and search for a biological marker of chemoresistance to such therapy. Gene expression profiling and molecular network analysis were used in the analysis of non-responders and responders with IFNAR2-positive HCC. The Wnt/beta-catenin signalling pathway contributed to resistance to IFN-alpha/5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/beta-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/beta-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3'-oxime (BIO)) induced chemoresistance to IFN-alpha/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-alpha/5-FU significantly to hepatoma cell cultures reduced the inhibitory effects of the latter two on DNA synthesis and accumulation of cells in the S-phase. The results indicate that activation of Wnt/beta-catenin signalling pathway induces chemoresistance to IFN-alpha/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.
authors.affiliation: Department of Surgery, Graduate School of Medicine and Health Science, Osaka University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Noda
authors.forename: H
authors.initials: H
authors.lastname: Nagano
authors.forename: I
authors.initials: I
authors.lastname: Takemasa
authors.forename: S
authors.initials: S
authors.lastname: Yoshioka
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.forename: H
authors.initials: H
authors.lastname: Wada
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: K
authors.initials: K
authors.lastname: Dono
authors.forename: K
authors.initials: K
authors.lastname: Umeshita
authors.forename: N
authors.initials: N
authors.lastname: Matsuura
authors.forename: K
authors.initials: K
authors.lastname: Matsubara
authors.forename: Y
authors.initials: Y
authors.lastname: Doki
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Monden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000502:physiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D051153:Wnt Proteins; D051176:beta Catenin; D053633:Receptor, Interferon alpha-beta; D005472:Fluorouracil