Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo

Yingying Mao^1*, Nana Pei^2*, Xinglu Chen^3*, Huiying Chen¹, Renhe Yan⁴, Na Bai⁵, Andrew Li⁶, Jinlong Li¹, Yanling Zhang¹, Hongyan Du¹, Baihong Chen¹, Colin Sumners⁷, Xuejun Wang^8✉, Shengqi Wang^8✉, Hongwei Li^1✉

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

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Citation:
Mao Y, Pei N, Chen X, Chen H, Yan R, Bai N, Li A, Li J, Zhang Y, Du H, Chen B, Sumners C, Wang X, Wang S, Li H. Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo. Int J Biol Sci 2018; 14(1):57-68. doi:10.7150/ijbs.22235. Available from https://www.ijbs.com/v14p0057.htm

Abstract

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