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

被引:99
|
作者
Noda, T. [1 ]
Nagano, H. [1 ]
Takemasa, I. [1 ]
Yoshioka, S. [1 ]
Murakami, M. [1 ]
Wada, H. [1 ]
Kobayashi, S. [1 ]
Marubashi, S. [1 ]
Takeda, Y. [1 ]
Dono, K. [1 ]
Umeshita, K. [2 ]
Matsuura, N. [3 ]
Matsubara, K. [4 ]
Doki, Y. [1 ]
Mori, M. [1 ]
Monden, M. [1 ]
机构
[1] Osaka Univ, Dept Surg, Grad Sch Med & Hlth Sci, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Dept Hlth Sci, Grad Sch Med & Hlth Sci, Suita, Osaka 5650871, Japan
[3] Osaka Univ, Dept Mol Pathol, Grad Sch Med & Hlth Sci, Suita, Osaka 5650871, Japan
[4] DNA Chip Res Inc, Kanagawa, Japan
关键词
hepatocellular carcinoma; combination therapy; interferon-alpha; 5-fluorouracil; chemoresistance; Wnt signalling; SUBCUTANEOUS INTERFERON-ALPHA; ADVANCED GASTRIC-CANCER; GENE-EXPRESSION; INTRAARTERIAL; 5-FLUOROURACIL; STEM-CELLS; EP-CAM; HEPATIC RESECTION; TUMOR THROMBUS; STAT3; ACTIVITY; IFN-ALPHA;
D O I
10.1038/sj.bjc.6605064
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. British Journal of Cancer (2009) 100, 1647-1658. doi: 10.1038/sj.bjc.6605064 www.bjcancer.com Published online 28 April 2009 (C) 2009 Cancer Research UK
引用
收藏
页码:1647 / 1658
页数:12
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