Conditionally Replicative Adenovirus Controlled by the Stabilization System of AU-Rich Elements Containing mRNA
Conditionally Replicative Adenovirus Controlled by the Stabilization System of AU-Rich Elements Containing mRNA
复制标题
DOI：
10.3390/cancers12051205
复制
发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Higashino, Fumihiro
中科院分区：
文献类型：
--
作者：
Mikawa, Yohei;Alam, Mohammad Towfik;Higashino, Fumihiro
富含Au的元素(Ares)是一种RNA元素，可以促进mRNAs的快速衰退，包括细胞生长和增殖所需的基因。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的稳定。在大多数癌细胞中，胞浆中的HUR水平上调，从而导致ARE-mRNA的稳定。我们研制了Adaret和AdAREF两种腺病毒，它们分别包括E1a基因3‘非翻译区的肿瘤坏死因子-α和c-fos基因。E1a蛋白在癌细胞中的表达高于正常细胞，在许多类型的癌细胞中病毒产生和细胞溶解活性也较高。ARE-mRNA稳定化的抑制导致病毒复制减少，表明稳定系统是生产病毒所必需的。在裸鼠体内形成的人类肿瘤的生长被瘤内注射Adaret和AdAREF所抑制。这些结果表明，在绝大多数ARE-mRNA稳定的癌症中，这些病毒具有作为溶瘤腺病毒的潜力。
AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNAs, including those of genes required for cell growth and proliferation. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the stabilization of ARE-mRNA. The level of HuR in the cytoplasm is up-regulated in most cancer cells, resulting in the stabilization of ARE-mRNA. We developed the adenoviruses AdARET and AdAREF, which include the ARE of TNF-alpha and c-fos genes in the 3 ' -untranslated regions of the E1A gene, respectively. The expression of the E1A protein was higher in cancer cells than in normal cells, and virus production and cytolytic activities were also higher in many types of cancer cells. The inhibition of ARE-mRNA stabilization resulted in a reduction in viral replication, demonstrating that the stabilization system was required for production of the virus. The growth of human tumors that formed in nude mice was inhibited by an intratumoral injection of AdARET and AdAREF. These results indicate that these viruses have potential as oncolytic adenoviruses in the vast majority of cancers in which ARE-mRNA is stabilized.