Hepatocellular carcinoma (HCC), the third leading cause of
cancer death in the world, is the most general type of primary
liver cancer. Although current treatment modalities, such as
liver transplantation, resection, percutaneous ablation, transarterial embolization,
chemotherapy and
radiotherapy are potentially curative, these methods are not universally applicable to all of HCC patients, especially for those with poor prognosis in which no effective remedy is available. Therefore, development of novel therapeutic approach for the treatment of HCC is urgently needed. In the current study, we developed a promising HCC-targeted gene therapy vector driven by
liver cancer-specific α-
fetoprotein promoter/enhancer coupled to an established platform technology. The activity of this expression vector is comparable with or even higher than that of strong cytomegalovirus (CMV) promoter and exhibits strong promoter activity in
liver cancer cells/
tumors, but has nearly no or very low activity in normal cells/organs in vitro and in orthotopic animal models in vivo. Its
cancer specificity exceeds that of the CMV promoter, which expresses non-specifically in both normal and
tumor cells. In addition, targeted expression of a therapeutic BikDD, a mutant of proapoptotic gene Bik effectively and preferentially killed
liver cancer cells, but not normal cells and significantly repressed growth of HCC
tumors, and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of HCC through intravenous systemic gene delivery. Importantly, systemic administration of BikDD by our expression vector exerted no systemically acute toxicity compared with CMV-BikDD in mice. Taken together, this study elucidates a relatively safe and highly effective and specific systemic gene therapy strategy for
liver cancer, and is worthy of further development for future clinical trials.