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Adenovirus‐mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo
Author(s) -
Jung ChoRok,
Yoo Jinsang,
Jang Ye Jin,
Kim Sangsoo,
Chu InSun,
Yeom Young Il,
Choi Jong Young,
Im DongSoo
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21137
Subject(s) - gene silencing , small interfering rna , cancer research , rna interference , in vivo , cytotoxic t cell , cell culture , biology , liver cancer , apoptosis , cancer , cancer cell , cell growth , in vitro , gene , hepatocellular carcinoma , transfection , rna , genetics
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 lines 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. (H EPATOLOGY 2006;43:1042–1052.)