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Open Access Research article

Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and pgk promoter: an in vitro and in vivo study

Wei Li12, Dao-Ming Li1, Kai Chen1, Zheng Chen2, Yang Zong2, Hong Yin1, Ze-Kuan Xu2, Yi Zhu2, Fei-Ran Gong345* and Min Tao16*

Author affiliations

1 Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China

2 Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

3 Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China

4 Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China

5 Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China

6 Institute of Medical Biotechnology, Soochow University, Suzhou, 215021, China

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Citation and License

BMC Cancer 2012, 12:547  doi:10.1186/1471-2407-12-547

Published: 23 November 2012

Abstract

Background

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 (AFP) 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 AFP promoter. It has been shown that linking the AFP enhancer with the promoter of the non-tissue-specific, human housekeeping phosphoglycerate kinase (pgk) gene can generate a strong and HCC-selective promoter.

Methods

We constructed a HCC-specific gene therapy system to target PP2A using the AFP enhancer/pgk promoter, and evaluated the efficiency and specificity of this system both in vitro and in vivo.

Results

AFP enhancer/pgk 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, AFP enhancer/pgk 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.

Conclusions

The novel approach of AFP enhancer/pgk promoter-driven expression of DN-PP2Acα may provide a useful cancer gene therapy strategy to selectively target HCC.

Keywords:
Hepatocellular carcinoma; AFP; Pgk; PP2A