Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study
<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Current therapies are insufficient, making HCC an intractable disease. Our previous studies confirmed that inhibition of protein phosphat...
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| Format: | Article |
| Language: | English |
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BMC
2012-11-01
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| Series: | BMC Cancer |
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| Online Access: | http://www.biomedcentral.com/1471-2407/12/547 |
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| author | Li Wei Li Dao-Ming Chen Kai Chen Zheng Zong Yang Yin Hong Xu Ze-Kuan Zhu Yi Gong Fei-Ran Tao Min |
| author_facet | Li Wei Li Dao-Ming Chen Kai Chen Zheng Zong Yang Yin Hong Xu Ze-Kuan Zhu Yi Gong Fei-Ran Tao Min |
| author_sort | Li Wei |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Current therapies are insufficient, making HCC an intractable disease. Our previous studies confirmed that inhibition of protein phosphatase 2A (PP2A) may provide a promising therapeutic strategy for cancer. Unfortunately, constitutive expression of PP2A in normal tissues limits the application of PP2A inhibition. Thus, a HCC-specific gene delivery system should be developed. The α-fetoprotein (<it>AFP</it>) promoter is commonly used in HCC-specific gene therapy strategies; however, the utility of this approach is limited due to the weak activity of the <it>AFP</it> promoter. It has been shown that linking the <it>AFP</it> enhancer with the promoter of the non-tissue-specific, human housekeeping phosphoglycerate kinase (<it>pgk</it>) gene can generate a strong and HCC-selective promoter.</p> <p>Methods</p> <p>We constructed a HCC-specific gene therapy system to target PP2A using the <it>AFP</it> enhancer/<it>pgk</it> promoter, and evaluated the efficiency and specificity of this system both <it>in vitro</it> and <it>in vivo</it>.</p> <p>Results</p> <p><it>AFP</it> enhancer/<it>pgk</it> promoter-driven expression of the dominant negative form of the PP2A catalytic subunit α (DN-PP2Acα) exerted cytotoxic effects against an AFP-positive human hepatoma cell lines (HepG2 and Hep3B), but did not affect AFP-negative human hepatoma cells (SK-HEP-1) or normal human liver cells (L-02). Moreover, <it>AFP</it> enhancer/<it>pgk</it> promoter driven expression of DN-PP2Acα inhibited the growth of AFP-positive HepG2 tumors in nude mice bearing solid tumor xenografts, but did not affect AFP-negative SK-HEP-1 tumors.</p> <p>Conclusions</p> <p>The novel approach of <it>AFP</it> enhancer/<it>pgk</it> promoter-driven expression of DN-PP2Acα may provide a useful cancer gene therapy strategy to selectively target HCC.</p> |
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| spelling | doaj.art-2bfb26c5760f404486c3443c447e811b2022-12-21T20:00:29ZengBMCBMC Cancer1471-24072012-11-0112154710.1186/1471-2407-12-547Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> studyLi WeiLi Dao-MingChen KaiChen ZhengZong YangYin HongXu Ze-KuanZhu YiGong Fei-RanTao Min<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Current therapies are insufficient, making HCC an intractable disease. Our previous studies confirmed that inhibition of protein phosphatase 2A (PP2A) may provide a promising therapeutic strategy for cancer. Unfortunately, constitutive expression of PP2A in normal tissues limits the application of PP2A inhibition. Thus, a HCC-specific gene delivery system should be developed. The α-fetoprotein (<it>AFP</it>) promoter is commonly used in HCC-specific gene therapy strategies; however, the utility of this approach is limited due to the weak activity of the <it>AFP</it> promoter. It has been shown that linking the <it>AFP</it> enhancer with the promoter of the non-tissue-specific, human housekeeping phosphoglycerate kinase (<it>pgk</it>) gene can generate a strong and HCC-selective promoter.</p> <p>Methods</p> <p>We constructed a HCC-specific gene therapy system to target PP2A using the <it>AFP</it> enhancer/<it>pgk</it> promoter, and evaluated the efficiency and specificity of this system both <it>in vitro</it> and <it>in vivo</it>.</p> <p>Results</p> <p><it>AFP</it> enhancer/<it>pgk</it> promoter-driven expression of the dominant negative form of the PP2A catalytic subunit α (DN-PP2Acα) exerted cytotoxic effects against an AFP-positive human hepatoma cell lines (HepG2 and Hep3B), but did not affect AFP-negative human hepatoma cells (SK-HEP-1) or normal human liver cells (L-02). Moreover, <it>AFP</it> enhancer/<it>pgk</it> promoter driven expression of DN-PP2Acα inhibited the growth of AFP-positive HepG2 tumors in nude mice bearing solid tumor xenografts, but did not affect AFP-negative SK-HEP-1 tumors.</p> <p>Conclusions</p> <p>The novel approach of <it>AFP</it> enhancer/<it>pgk</it> promoter-driven expression of DN-PP2Acα may provide a useful cancer gene therapy strategy to selectively target HCC.</p>http://www.biomedcentral.com/1471-2407/12/547Hepatocellular carcinomaAFPPgkPP2A |
| spellingShingle | Li Wei Li Dao-Ming Chen Kai Chen Zheng Zong Yang Yin Hong Xu Ze-Kuan Zhu Yi Gong Fei-Ran Tao Min Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study BMC Cancer Hepatocellular carcinoma AFP Pgk PP2A |
| title | Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study |
| title_full | Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study |
| title_fullStr | Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study |
| title_full_unstemmed | Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study |
| title_short | Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and <it>pgk</it> promoter: an <it>in vitro</it> and <it>in vivo</it> study |
| title_sort | development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2a using the α fetoprotein promoter enhancer and it pgk it promoter an it in vitro it and it in vivo it study |
| topic | Hepatocellular carcinoma AFP Pgk PP2A |
| url | http://www.biomedcentral.com/1471-2407/12/547 |
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