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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.

bmc cancer

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