AAV-Mediated angiotensin 1-7 overexpression inhibits tumor growth of lung cancer in vitro and in vivo

Abstract

Ang-(1-7) inhibits lung cancer cell growth both in vitro and in vivo. However, the molecular mechanism of action is unclear and also the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Here, we have demonstrated that Ang- (1-7) inhibits lung cancer cell growth by interrupting pre-replicative complex assembly and restrains epithelial-mesenchymal transition via Cdc6 inhibition. Furthermore, we constructed a mutant adeno-associated viral vector AAV8 (Y733F) that produced stable and high efficient Ang-(1-7) expression in a xenograft tumor model. The results show that AAV8-mediated Ang-(1-7) over-expression can remarkably suppress tumor growth in vivo by down-regulating Cdc6 and anti-angiogenesis. Ang-(1-7) over-expression via the AAV8 method may be a promising strategy for lung cancer treatment.

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

“…Adeno-associated virus (AAV) is one of the most versatile vectors for in vivo gene therapy. Our previous study demonstrated that administration of AAV8-Ang-(1-7) significantly attenuated the growth of human nasopharyngeal carcinoma (NPC) xenograft tumors and non-small cell lung cancer (NSCLC), suggesting that AAV-mediated Ang-(1-7) gene therapy is potentially effective and useful for cancer treatment 6 , 7 . In this study, we first reported the in vivo anti-tumor efficacy of Ang-(1-7) mediated by the optimized AAV8 in a murine H22 hepatoma model.…”

“…The renin-angiotensin system (RAS) has been identified to play an important role in the pathogenesis of cancers, including prostate cancer, lung cancer, nasopharyngeal carcinoma and others 5 - 7 . Angiotensin-(1-7) [Ang-(1-7)], an endogenous heptapeptide hormone of the RAS, mediates both vasodilation and anti-proliferative effects by activating a distinct plasma membrane G protein-coupled receptor identified as the Mas receptor (MasR) 8 , 9 .…”

“…Angiotensin-(1-7) [Ang-(1-7)], an endogenous heptapeptide hormone of the RAS, mediates both vasodilation and anti-proliferative effects by activating a distinct plasma membrane G protein-coupled receptor identified as the Mas receptor (MasR) 8 , 9 . There is a growing body of evidence suggesting that Ang-(1-7) exerts anti-tumor effects in a variety of cancers, mainly through its anti-proliferative and anti-angiogenic actions 6 , 7 . In fact, a phase I/II clinical trial has confirmed the effectiveness and safety of Ang-(1-7) in patients with advanced solid tumors 10 - 12 .…”

Zika Virus Envelope Protein induces G2/M Cell Cycle Arrest and Apoptosis via an Intrinsic Cell Death Signaling Pathway in Neuroendocrine PC12 Cells

“…PC12 cells were collected 48 h post-transfection and fixed with 4% paraformaldehyde (Solarbio, China) for 20 min, permeabilized with 0.1% Triton X-100 (Biosharp, China) for 15 min. Immunostaining was then done on the fixed cells as detailed previously 23 using a monoclonal antibody against 6×His tag (1: 500, Abcam, US) followed by Alexa Fluor 633 anti-mouse IgG (1:1,000; ThermoFisher Scientific, US) as the secondary antibody. Nuclei DNA staining was performed with 4', 6-diamidino-2-phenylindole (DAPI, Sigma-Aldrich, US).…”

“…Total RNA was isolated from transduced PC12 cells using TRIzol® (Sigma, US), and then converted into cDNA with iScript™ Select cDNA Synthesis Kit (Bio-Rad, US). Quantitative real-time RT-PCR was performed on an ABI 7500 real-time PCR system (Applied Biosystems, US) as described previously 23 . Primers for target genes ( Bax, Bcl-2, Cyclin B1, p53, p21 and β-actin ) are listed in Table 1 .…”