Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma.
Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma.
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DOI：
10.1038/sj.bjc.6605064
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发表时间：
2009-05-19
影响因子：
8.8
通讯作者：
Monden, M.
中科院分区：
文献类型：
--
作者：
Noda, T.;Nagano, H.;Takemasa, I.;Yoshioka, S.;Murakami, M.;Wada, H.;Kobayashi, S.;Marubashi, S.;Takeda, Y.;Dono, K.;Umeshita, K.;Matsuura, N.;Matsubara, K.;Doki, Y.;Mori, M.;Monden, M.
关键词：
I型IFN受体2（IFNAR 2）表达与干扰素（IFN）-α/5-氟尿嘧啶（5-FU）联合治疗肝细胞癌（HCC）的临床反应显著相关。然而，一些IFNAR 2阳性患者对治疗没有反应。这一结果表明，可能有其他因素，这将是负责对IFN-α/5-FU治疗耐药。本研究旨在探讨IFN-α/5-FU抗肿瘤细胞增殖的作用机制，寻找肿瘤细胞对IFN-α/5-FU耐药的生物学标志物。基因表达谱和分子网络分析用于分析IFNAR 2阳性HCC的无应答者和应答者。Wnt/β-catenin信号通路参与了IFN-α/5-FU治疗的耐药性。免疫组织化学分析显示，阳性上皮细胞粘附分子（Ep-CAM）表达，Wnt/β-连环蛋白信号转导的靶分子，仅在无应答者中。体外研究表明，糖原合成激酶3抑制剂（6-溴靛玉红-3 ′-肟（BIO））激活Wnt/β-catenin信号通路可诱导IFN-α/5-FU耐药。以BrdU为基础的细胞增殖ELISA和细胞周期分析表明，同时加入BIO和IFN-α/5-FU可显著降低后两者对S期细胞DNA合成和积累的抑制作用。结果表明，Wnt/β-catenin信号通路的激活诱导了对IFN-α/5-FU治疗的化学抗性，并且表明Ep-CAM是对这种治疗的抗性的潜在有用的标记物，特别是在IFNAR 2阳性的病例中。
Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α/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-α/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α/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/β-catenin signalling pathway contributed to resistance to IFN-α/5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/β-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/β-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α/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/β-catenin signalling pathway induces chemoresistance to IFN-α/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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EP-CAM：人类上皮抗原是一种同粒细胞粘附分子。
影响因子：
7.8
作者：
Litvinov, S V;Velders, M P;Bakker, H A;Fleuren, G J;Warnaar, S O
通讯作者：
Warnaar, S O