Adeno-associated virus-mediated expression of kallistatin suppresses local and remote hepatocellular carcinomas
| Autor: | Xuesong Dong, Ruian Xu, Xueying Sun, Hongchi Jiang, Farzin Farzaneh, Peter W.C. Fung, Lai Yin Tse |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Carcinoma Hepatocellular Angiogenesis viruses Genetic enhancement Apoptosis medicine.disease_cause Mice Transduction Genetic Cell Line Tumor Drug Discovery Genetics medicine Animals Humans Molecular Biology Adeno-associated virus Serpins Genetics (clinical) Cell Proliferation Mice Inbred BALB C business.industry Genetic Therapy Transfection Dependovirus medicine.disease digestive system diseases Angiogenesis inhibitor Kallistatin Hepatocellular carcinoma Immunology Cancer research Molecular Medicine business |
| Zdroj: | The Journal of Gene Medicine. 10:508-517 |
| ISSN: | 1521-2254 1099-498X |
| DOI: | 10.1002/jgm.1180 |
| Popis: | Background The current treatments for hepatocellular carcinoma (HCC) are poor, particularly for metastatic HCC. Intraportal transfusion of adeno-associated virus (AAV) leads to long-term and persistent transgenic expression in livers. Kallistatin, a novel angiogenesis inhibitor, exhibits anti-tumor activity. The aim of the study was to investigate whether intraportal injection of AAV-kallistatin could suppress local and metastatic HCC in mice. Methods An AAV vector encoding kallistatin was constructed, and its transduction efficiency by intraportal transfusion in livers was examined by RT-PCR, immunohistochemical and Western blotting analysis. The anti-tumor activity was tested in three HCC models including hepatic and subcutaneous human Hep3B HCC tumors in BALB/c athymic (nu/nu) mice, and subcutaneous mouse BNL HCC tumors in BALB/c mice. Tumor cell proliferation in situ was examined by anti-Ki-67 staining, and apoptosis by TUNEL. Results Gene transfection by rAAV-kallistatin inhibited proliferation of human umbilical vein endothelial cells and HCC cells in vitro. Intraportal injection of rAAV-kallistatin resulted in persistent and specific expression of kallistatin in livers detected by RT-PCR and immunohistochemical analysis, and kallistatin protein in circulation detected by Western blotting analysis. Intraportal injection of rAAV-kallistatin significantly suppressed angiogenesis and growth of hepatic Hep3B tumors. The kallistatin released by hepatocytes into the circulation suppressed remote Hep3B and BNL tumors established subcutaneously. The rAAV-kallistatin gene therapy significantly inhibited tumor cell proliferation and induced apoptosis. Conclusions Intraportal injection of rAAV-kallistatin suppressed hepatic and subcutaneous HCC tumors, relying on its anti-angiogenic and anti-proliferative activities. Copyright © 2008 John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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