Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma

Br J Cancer. 2009 May 19;100(10):1647-58. doi: 10.1038/sj.bjc.6605064. Epub 2009 Apr 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / physiology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / physiology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Epithelial Cell Adhesion Molecule
  • Female
  • Fluorouracil / administration & dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interferon-alpha / administration & dosage
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Male
  • Middle Aged
  • Mutation / physiology
  • Oligonucleotide Array Sequence Analysis
  • Receptor, Interferon alpha-beta / genetics
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Wnt Proteins / genetics
  • Wnt Proteins / physiology*
  • beta Catenin / genetics
  • beta Catenin / physiology*

Substances

  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • IFNAR2 protein, human
  • Interferon-alpha
  • Wnt Proteins
  • beta Catenin
  • Receptor, Interferon alpha-beta
  • Fluorouracil