Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo
Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo
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DOI：
10.1002/hep.21137
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发表时间：
2006-05-01
期刊：
影响因子：
13.5
通讯作者：
Iml, DS
中科院分区：
文献类型：
--
作者：
Jung, CR;Yoo, J;Iml, DS
垂体肿瘤转化 (PTTG) 基因家族包括 PTTG1、2 和 3。PTTG1 (securin) 的强制表达可诱导细胞转化并促进动物模型中的肿瘤发展。 PTTG1 在多种人类癌症中过度表达。然而，PTTG基因家族在肝细胞癌中的表达和致病意义尚不清楚。使用短干扰RNA (siRNA) 进行基因沉默已成为研究基因功能的有效手段，并越来越多地用于癌症基因治疗方法。我们报告说，PTTG1（而非 PTTG2 和 3）在患者肝癌组织中高表达且频繁表达，并且在 SH-J1、SK-Hep1 和 Huh-7 肝癌细胞系中高表达。编码针对 PTTG1 的 siRNA (Ad.PTTG1-siRNA) 的腺病毒载体在 SH-J1 肝癌细胞中特异性且有效地耗尽 PTTG1，从而导致 p53 激活，从而导致 p21 表达增加并诱导细胞凋亡。 HCT116 结直肠癌细胞中 PTTG1 的缺失以 p53 依赖性方式表现出细胞毒性作用。 Ad.PTTG1-siRNA 介导的细胞毒作用依赖于肝癌细胞系中 PTTG1 和 p53 的表达水平。 Huh-7肝癌细胞一旦用Ad.PTTG1-siRNA转导，在裸鼠中表现出明显减弱的生长潜力。 Ad.PTTG1-siRNA 的肿瘤内递送显着抑制了在裸鼠中建立的 SH-J1 肿瘤异种移植物中的肿瘤生长。总之，肝癌细胞中过表达的PTTG1负向调节p53诱导细胞凋亡的能力。使用 siRNA 进行 PTTG1 基因沉默可能是治疗 PTTG1 大量表达的肝癌的有效方法。
The pituitary tumor transforming (PTTG) gene family comprises PTTG1, 2, and 3. Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models. PTTG1 is overexpressed in various human cancers. However, the expression and pathogenic implications of the PTTG gene family in hepatocellular carcinoma are largely unknown. Gene silencing using short interfering RNA (siRNA) has become an efficient means to study the functions of genes and has been increasingly used for cancer gene therapy approaches. We report that PTTG1, but not PTTG2 and 3, was highly and frequently expressed in liver cancer tissues from patients and highly in SH-J1, SK-Hep1, and Huh-7 hepatoma cell lines. Adenoviral vector encoding siRNA against PTTG1 (Ad.PTTG1-siRNA) depleted PTTG1 specifically and efficiently in SH-J1 hepatoma cells, which resulted in activation of p53 that led to increased p21 expression and induction of apoptosis. The depletion of PTTG1 in HCT116 colorectal cancer cells exhibited a cytotoxic effect in a p53-dependent manner. Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines. Huh-7 hepatoma cells, once transduced with Ad.PTTG1-siRNA, displayed markedly attenuated growth potential in nude mice. Intra-tumor delivery of Ad.PTTG1-siRNA led to significant inhibition of tumor growth in SH-J1 tumor xenograft established in nude mice. In conclusion PTTG1 overexpressed in hepatoma cell tines negatively regulates the ability of p53 to induce apoptosis. PTTG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed.