Cancer targeting Gene-Viro-Therapy specific for liver cancer by α-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24
Cancer targeting Gene-Viro-Therapy specific for liver cancer by α-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24
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DOI：
10.1093/abbs/gmr071
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发表时间：
2011-10-01
影响因子：
3.7
通讯作者：
Liu, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Cao, Xin;Wei, Ruicheng;Liu, Xin-Yuan
基因治疗与病毒治疗相结合治疗癌症受到密切关注，已成为癌症生物治疗领域的趋势。已经提出了一种称为“癌症靶向基因病毒疗法”（CTGVT）或“基因武装溶瘤病毒疗法”（GAOVT）的策略，其中将抗肿瘤基因插入溶瘤病毒载体中。在我们前期的研究中，成功构建了一种对正常细胞具有增强的安全性和严格的肝癌靶向能力的双调控溶瘤腺病毒，命名为Ad center dot enAFP center dot E1A center dot E1B (Delta 55)（简称Ad center dot enAFP center dot D55）。在目前的工作中，白介素24（IL-24）和细胞因子信号传导抑制因子3（SOCS3）基因被包装到Ad中心点enAFP中心点D55中。与溶瘤病毒载体Ad center dot enAFP center dot D55相比，新的构建体Ad center dot enAFP center dot D55-(IL-24)和Ad center dot enAFP center dot D55-(SOCS3)在肝癌细胞系中显示出改善的杀肿瘤活性。 Ad center dot enAFP center dot D55-(IL-24)和Ad center dot enAFP center dot D55-(SOCS3)的共同给药在体外和裸鼠异种移植模型中均表现出比单独使用Ad center dot enAFP center dot D55-(IL-24)或Ad center dot enAFP center dot D55-(SOCS3)更好的抗肿瘤效果。此外，我们的结果还表明，HuH-7细胞中Ad center dot enAFP center dot D55-(SOCS3)感染阻断Jak/Stat3途径可以下调一些抗凋亡蛋白，例如XIAP、Bcl-xL和survivin，这可能使细胞对Ad center dot enAFP center dot D55-(IL-24)诱导的细胞凋亡敏感。这些结果表明Ade中心点nAFP中心点D55-(IL-24)和Ad中心点enAFP中心点D55-(SOCS3)的共同施用可以作为治疗肝癌的候选治疗方法。
The combination of gene therapy and virotherapy for cancer treatment has received close attention and has become a trend in the field of cancer biotherapy. A strategy called 'Cancer Targeting Gene-Viro-Therapy' (CTGVT) or 'Gene Armed Oncolytic Viral Therapy' (GAOVT) has been proposed, in which an antitumor gene is inserted into an oncolytic viral vector. In our previous study, a dual-regulated oncolytic adenovirus with enhanced safety for normal cells and strict liver cancer-targeting ability, designated Ad center dot enAFP center dot E1A center dot E1B (Delta 55) (briefly Ad center dot enAFP center dot D55), was successfully constructed. In the current work, interleukin-24 (IL-24) and suppressor of cytokine signaling 3 (SOCS3) genes were packaged into Ad center dot enAFP center dot D55. The new constructs, Ad center dot enAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3), showed improved tumoricidal activity in hepatoma cell lines compared with the oncolytic viral vector Ad center dot enAFP center dot D55. The co-administration of Ad center dot enAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3) showed much better antitumor effect than Ad center dot enAFP center dot D55-(IL-24) or Ad center dot enAFP center dot D55-(SOCS3) alone both in vitro and in a nude mouse xenograft model. Moreover, our results also showed that blockade of the Jak/ Stat3 pathway by Ad center dot enAFP center dot D55-(SOCS3) infection in HuH-7 cells could down-regulate some anti-apoptosis proteins, such as XIAP, Bcl-xL, and survivin, which might sensitize the cells to Ad center dot enAFP center dot D55-(IL-24)-induced apoptosis. These results indicate that co-administration of Ade center dot nAFP center dot D55-(IL-24) and Ad center dot enAFP center dot D55-(SOCS3) may serve as a candidate therapeutic approach for the treatment of liver cancer.