Chen Yangchao, Lin Marie C, Yao Hong, Wang Hua, Zhang Ai-Qun, Yu Jun, Hui Chee-kin, Lau George K, He Ming-liang, Sung Joseph, Kung Hsiang-fu
Stanley Ho Center for Emerging Infectious Diseases, Hong Kong, China.
Hepatology. 2007 Jul;46(1):200-8. doi: 10.1002/hep.21668.
Enhancer of zeste homolog 2 (EZH2) has been shown to be overexpressed 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.
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.
已证明zeste同源物2增强子（EZH2）在肝细胞癌（HCC）中过表达。我们研究了EZH2在HCC肿瘤发生中的潜在作用，并探讨了靶向EZH2的RNA干扰（RNAi）作为一种HCC治疗形式的有效性。采用慢病毒介导的RNAi敲低人肝癌细胞中EZH2的表达，以研究EZH2在肿瘤发生中的功能并评估治疗效果。慢病毒介导的RNAi有效降低了EZH2的表达。抑制HCC细胞中的EZH2可显著降低其体外生长速率，并明显减弱其体内致瘤性。此外，在已建立的大型HCC小鼠模型中，我们表明瘤内注射靶向EZH2的慢病毒（Lenti）-短发夹RNA（shRNA）或小干扰RNA（siRNA）可产生显著的肿瘤消退。为了解其分子作用机制，我们采用蛋白质组分析技术，发现Stathmin 1是EZH2的下游靶点，因为Lenti-shEZH2处理降低了Stathmin蛋白表达，而Stathmin的异位过表达阻止了Lenti-shEZH2介导的肿瘤生长抑制。
我们的研究结果首次表明EZH2在HCC肿瘤发生中起关键作用，并且是HCC的一个新的治疗靶点。
