Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin
Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin
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DOI：
10.1002/hep.21668
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发表时间：
2007-07-01
期刊：
影响因子：
13.5
通讯作者：
Kung, Hsiang-fu
中科院分区：
文献类型：
--
作者：
Chen, Yangchao;Lin, Marie C.;Kung, Hsiang-fu
Zeste增强子同源物2（EZH 2）已被证明在肝细胞（HCC）中过表达。我们研究了EZH 2在HCC肿瘤发生中的潜在作用，并检查了靶向EZH 2的RNA干扰（RNAi）作为HCC治疗形式的有用性。利用慢病毒介导的RNAi技术，敲低EZH 2在人肝癌细胞中的表达，研究EZH 2在肿瘤发生中的作用，并评价其治疗效果。慢病毒介导的RNAi有效地降低了EZH 2的表达。抑制HCC细胞中的EZH 2显著降低其体外生长速率，并显著降低其体内致瘤性。此外，在已建立的大尺寸HCC小鼠模型中，我们发现肿瘤内注射靶向EZH 2的慢病毒（Lenti）-shRNA（短发夹RNA）或siRNA（小干扰RNA）可产生显著的肿瘤消退。为了理解其分子作用机制，我们采用蛋白质组学分析技术，发现stathmin 1是EZH 2的下游靶标，因为Lenti-shEZH 2处理降低了stathmin蛋白表达，并且stathmin的异位过表达阻止了Lenti-shEZH 2介导的肿瘤生长抑制。结论：我们的研究结果首次表明EZH 2在HCC肿瘤发生中起关键作用，并且是HCC的新治疗靶点。
Enhancer of zeste homolog 2 (EZH2) has been shown to be overexprcssed in hepatocellular (HCC). We investigated the potential role of EZH2 in HCC tumorigenesis and examined the usefulness of RNA interference (RNAi) targeting EZH2 as a form of HCC treatment. Lentivirus-mediated RNAi was employed to knock-down EZH2 expression in human hepatoma cells to study the function of EZH2 in tumorigenesis and evaluate the treatment efficacy. Lentivirus-mediated RNAi effectively reduced EZH2 expression. Suppression of EZH2 in HCC cells significantly reduced their growth rate in vitro and markedly diminished their tumorigenicity in vivo. Moreover, in a mice model of established large-sized HCC, we showed that intratumor injection of lentiviral (Lenti)-shRNA (short hairpin RNA) or siRNA (small interfering RNA) targeting EZH2 produced significant tumor regression. To understand its molecular mechanism of action, we employed proteomic profiling technique and found that stathmin 1 is the downstream target of EZH2, as Lenti-shEZH2 treatment decreased stathmin protein expression, and ectopic overexpression of stathmin prevented Lenti-shEZH2 mediated tumor growth inhibition. Conclusion: Results from our study suggested for the first time that EZH2 plays a key role in HCC tumorigenesis, and is a novel therapeutic target for HCC.