Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma.
Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma.
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DOI：
10.1158/0008-5472.can-10-0749
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
--
作者：
Lee YH;Andersen JB;Song HT;Judge AD;Seo D;Ishikawa T;Marquardt JU;Kitade M;Durkin ME;Raggi C;Woo HG;Conner EA;Avital I;Maclachlan I;Factor VM;Thorgeirsson SS
发展肝细胞癌的靶向治疗仍然是一个主要的挑战。泛素化调节因子COP1通过泛素化调节P53的活性，在人肝细胞癌中经常过表达。在这项研究中，我们验证了一种假设，即通过siRNA介导的抑制来阻断COP1可能会影响肝癌的进展过程。在几种肝癌细胞系中，COP1亚型COP1-1被选为siRNAs最有效的抑制生长和诱导凋亡的靶点。保留野生型P53或表达突变型P53(Y220C或R249S)的肝癌细胞生长受到抑制，而P53缺失的Hep3B细胞耐药。微阵列表达分析显示，COPI-1阻断的抗增殖作用是由一组常见的分子改变驱动的，包括与P53相关的功能网络。在原位移植的小鼠肝细胞癌模型中，通过稳定的核酸-脂质颗粒(SNALP)系统地递送修饰的COP1 siRNA可以抑制肝脏中的肿瘤生长，而不会产生不必要的免疫反应。我们的发现首次证明了COP1可以成为肝癌系统治疗的一个有前途的靶点。
Development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study we tested the hypothesis that COP1 blockade by siRNA-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53 null Hep3B cells were resistant. Microarray expression analysis revealed that the anti-proliferative effects of COPI-1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic-acid-lipid particles (SNALP) suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC.