Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells.
Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells.
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DOI：
10.1186/1476-4598-8-76
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发表时间：
2009-09-24
期刊：
影响因子：
37.3
通讯作者：
So SK
中科院分区：
文献类型：
--
作者：
Wei W;Chua MS;Grepper S;So SK
肝细胞癌（HCC）是一种侵袭性癌症，是全球第三大癌症死亡原因。标准治疗无效的部分原因是HCC对常规化疗具有内在抗性。其不良预后和有限的治疗选择使得开发新的和选择性的化疗药物至关重要。由于Wnt/β-catenin通路在HCC的发生中是必不可少的，因此我们研究了Wnt-1介导的信号传导的抑制作为HCC中的潜在分子靶点。我们证明了Wnt-1在人肝癌细胞系和人HCC组织的亚组中与配对的相邻非肿瘤组织相比是高表达的。抗Wnt-1抗体剂量依赖性地降低过表达Wnt-1并携带野生型β-连环蛋白的Huh 7和Hep 40细胞的活力和增殖，但不影响Wnt-1表达不可检测的正常肝细胞。抗Wnt-1抗体处理后，Huh 7和Hep 40细胞中也观察到凋亡。在这两种细胞系中，抗Wnt-1抗体降低了β-catenin/Tcf 4转录活性，这与内源性β-catenin/Tcf 4靶基因c-Myc、细胞周期蛋白D1和生存素的下调有关。瘤内注射抗Wnt-1抗体可抑制Huh 7异种移植模型中的体内肿瘤生长，这也与细胞凋亡和c-Myc、细胞周期蛋白D1和生存素表达减少有关。我们的研究结果表明，Wnt-1是肝癌细胞的存活因子，并且阻断Wnt-1介导的信号传导可能为治疗过表达Wnt-1的肝癌亚组提供潜在的途径特异性治疗策略。
Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/β-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC. We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type β-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased β-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous β-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions. Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.
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