Activation of WntΒ-catenin signalling pathway induces chemoresistance to interferon-α5-fluorouracil combination therapy for hepatocellular carcinoma

T. Noda, H. Nagano, I. Takemasa, S. Yoshioka, M. Murakami, H. Wada, S. Kobayashi, S. Marubashi, Y. Takeda, K. Dono, K. Umeshita, N. Matsuura, K. Matsubara, Y. Doki, M. Mori, M. Monden

研究成果: Contribution to journalArticle査読

101 被引用数 (Scopus)

抄録

Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α5-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-α5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α5-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 WntΒ-catenin signalling pathway contributed to resistance to IFN-α5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of WntΒ-catenin signalling, only in non-responders. In vitro studies showed that activation of WntΒ-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α5-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 WntΒ-catenin signalling pathway induces chemoresistance to IFN-α5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.

本文言語英語
ページ(範囲)1647-1658
ページ数12
ジャーナルBritish journal of cancer
100
10
DOI
出版ステータス出版済み - 5 19 2009
外部発表はい

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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