Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells.
Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells.
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DOI：
10.3892/or.2018.6865
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发表时间：
2018-11
期刊：
影响因子：
4.2
通讯作者：
Aya Yanagawa-Matsuda;Yohei Mikawa;U. Habiba;T. Kitamura;M. Yasuda;Mohammad Towfik-Alam;Y. Kitagawa;K. Minowa;M. Shindoh;F. Higashino
中科院分区：
文献类型：
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作者：
Aya Yanagawa-Matsuda;Yohei Mikawa;U. Habiba;T. Kitamura;M. Yasuda;Mohammad Towfik-Alam;Y. Kitagawa;K. Minowa;M. Shindoh;F. Higashino
富含Au的元素(Ares)是一种RNA元素，可以促进mRNA的快速衰变。ARE-mRNA的命运由ARE结合蛋白控制。HUR是胚胎致死性视觉异常(ELAV)RNA结合蛋白家族的成员，参与ARE-mRNA的输出和稳定。在绝大多数癌细胞中，HUR结构性地重新定位到细胞质中，导致ARE-mRNA的稳定。以前，我们描述了病毒复制所必需的腺病毒基因产物E4orf6参与ARE-mRNA的输出和稳定。在本研究中，我们展示了E4orf6缺失腺病毒d1355的溶瘤潜力，它有望在癌细胞中选择性复制。D1355在癌细胞中的病毒产量和杀细胞活性均高于正常细胞。HUR-耗竭下调了d1355的复制，表明ARE-mRNA的稳定是生产这种病毒所必需的。瘤内注射d1355可抑制裸鼠体内肿瘤生长。此外，D1355比E1B55k缺失腺病毒具有更强的溶瘤作用。这些结果表明，DL355有可能作为一种溶瘤腺病毒来治疗大量ARE-mRNA稳定的癌症。
AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA. In the vast majority of cancer cells, HuR constitutively relocates to the cytoplasm, resulting in the stabilization of ARE-mRNA. Previously, we described that the adenovirus gene product, E4orf6, which is necessary for virus replication, participates in ARE-mRNA export and stabilization. In the present study, we showed the oncolytic potential of E4orf6-deleted adenovirus dl355, which is expected to be replicated selectively in cancer cells. Virus production and cytolytic activity of dl355 were higher in cancer cells than in normal cells. HuR-depletion downregulated dl355 replication, demonstrating that ARE-mRNA stabilization is required for the production of this virus. Tumor growth was inhibited in nude mice by an intratumoral injection of dl355. Furthermore, dl355 had a stronger oncolytic effect than E1B55k-deleted adenovirus. These results indicate that dl355 has potential as an oncolytic adenovirus for a large number of cancers where ARE-mRNA is stabilized.