Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo.
Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo.
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DOI：
10.7150/ijbs.22235
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发表时间：
2018
影响因子：
9.2
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
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
背景：血管紧张素-（1-7）[Ang-（1-7）]在体内外均能抑制多种肿瘤细胞的生长。然而，Ang-（1-7）在体内的快速降解限制了其临床应用。腺相关病毒（AAV）血清型-8是用于长期体内基因递送的显著载体。方法：本研究旨在探讨腺相关病毒介导的Ang-（1-7）过表达对肝癌细胞的影响。我们首先产生了AAV 8的三种不同的酪氨酸（Y）至苯丙氨酸（F）突变体（Y 447 F、Y 703 F、Y 708 F），并评估了它们的体内转导效率。结果如下：数据表明，与野生型AAV 8（wtAAV 8）相比，Y 703 F突变体引起肝脏基因递送的显著增强。以H22肝癌小鼠为模型，研究了重组载体介导的Ang-（1-7）的抗肿瘤作用。我们的结果表明，AAV-Ang-（1-7）通过显着下调血管生成来持续抑制肝细胞癌的生长。这通过观察到的促血管生成因子VEGF和PIGF水平的降低而得到证实。结论：总的来说，这些数据表明，由于其长期和显著的抗肿瘤活性，由优化载体介导的Ang-（1-7）过表达可能是肝细胞癌治疗的有效替代方案。
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.
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影响因子：
4.4
作者：
Deng, Wen-Tao;Dinculescu, Astra;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
影响因子：
12.4
作者：
Petrs-Silva, Hilda;Dinculescu, Astra;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
比较肾脏中与酪氨酸突变腺相关病毒血清型载体的转导效率的比较。
影响因子：
2.9
作者：
Qi YF;Li QH;Shenoy V;Zingler M;Jun JY;Verma A;Katovich MJ;Raizada MK
通讯作者：
Raizada MK
影响因子：
5.7
作者：
Pei, Nana;Wan, Renqiang;Li, Hongwei
通讯作者：
Li, Hongwei
影响因子：
--
作者：
Sen, Dwaipayan;Gadkari, Rupali A.;Jayandharan, Giridhara R.
通讯作者：
Jayandharan, Giridhara R.