Int J Biol Sci 2018; 14(1):57-68. doi:10.7150/ijbs.22235 This issue
Research Paper
1. School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China;
2. Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China;
3. Clinical Laboratory,The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China;
4. Guangzhou Bioneeds Biotechnology CO., LTD, Guangzhou, Guangdong, China;
5. Deparement of Nuclear Medicine, People's Hospital of Yuxi City, Yuxi, Yunnan, China.
6. Department of Biomedical Engineering, The Johns University School of Medicine, Baltimore, USA;
7. Departments of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA.
8. Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China.
*These authors contributed equally to this work
Background: Angiotensin-(1-7) [Ang-(1-7)] has been identified to inhibit the growth of many types of tumor cells both in vitro and in vivo. However, the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Adeno-associated virus (AAV) serotype-8 is a remarkable vector for long-term in vivo gene delivery.
Method: This study was designed to investigate the effects of AAV-mediated Ang-(1-7) overexpression on hepatocellular carcinoma. We first generated three different tyrosine (Y) to phenylalanine (F) mutants of AAV8 (Y447F, Y703F, Y708F) and evaluated their in vivo transduction efficiencies.
Results: The data indicated that the Y703F mutant elicited a significant enhancement of liver gene delivery when compared with wild-type AAV8 (wtAAV8). The anti-tumor effect of Ang-(1-7) mediated by this optimized vector was evaluated in H22 hepatoma-bearing mice. Our results demonstrated that AAV-Ang-(1-7) persistently inhibited the growth of hepatocellular carcinoma by significantly downregulating angiogenesis. This was confirmed by observed decreases in the levels of the proangiogenic factors VEGF and PIGF.
Conclusion: Collectively, these data suggest that Ang-(1-7) overexpression mediated by the optimized vector may be an effective alternative for hepatocellular carcinoma therapy due to its long-term and significant anti-tumor activity.
Keywords: angiotensin-(1-7), hepatocellular carcinoma, adeno-associated virus, gene therapy