Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer
Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer
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DOI：
10.1158/1535-7163.mct-16-0383
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发表时间：
2017-01-01
影响因子：
5.7
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Machitani, Mitsuhiro;Sakurai, Fuminori;Mizuguchi, Hiroyuki
溶瘤病毒作为一种潜在的肿瘤治疗药物受到了广泛的关注。在各种类型的溶瘤病毒中，携带肿瘤特异性启动子驱动的E1基因表达盒的端粒酶特异性复制型腺病毒（TRAD）表现出有效的抗肿瘤作用。显示出更高的复制效率和抗肿瘤活性的新型TRAD的开发对于更安全和更有效的癌症治疗将是非常有益的。我们最近证明，内切核糖核酸酶Dicer通过加工病毒相关（VA）-RNA（Ad编码的小非编码RNA）显著抑制野生型腺病毒（Ad）的复制，并且Dicer的敲低导致野生型Ad感染后增强的VA-RNA表达和Ad复制。基于这些发现，我们在此开发了表达针对Dicer的shorthairpin RNA的新型TRAD（shDicer; TRAD-shDicer）。感染后，TRAD-shDicer有效地诱导Dicer的敲低。与传统TRAD相比，TRAD-shDicer在肿瘤细胞中显示出显著更高的复制效率和肿瘤细胞裂解活性。用TRAD-shDicer感染正常细胞不改变Dicer表达水平和活力。这些结果表明TRAD-shDicer由于其增强的溶瘤活性而成为有效的抗肿瘤试剂。(C)2016年AACR。
Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter- driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. (C) 2016 AACR.