title: The application of multiple miRNA response elements enables oncolytic adenoviruses to possess specificity to glioma cells.
abstract: Adenovirus-mediated virotherapy is one of the promising therapeutic approaches for glioma treatment. However, its replication efficiency and specificity still failed to meet the requirements for clinical treatment. To improve the anti-tumor activity and specificity of oncolytic adenoviruses (OA), we applied multiple miRNA response elements (MREs) of miR-124, miR-128, miR-146b and miR-218, whose expressions were downregulated in glioma cells, to enable OA to be specific to glioma. Adenoviral E1A protein regulated by these 4 MREs (OA-4MREs) was shown to be highly expressed in glioma cells, but not in normal cells. The selective E1A expression led to glioma-specific replication and cytotoxicity of OA-4MREs. Animal experiments also showed that OA-4MREs exhibited improved anti-tumor activities for both subcutaneous and intracranial glioma xenografts, without significant toxicity to normal brain and liver tissues. Collectively, we demonstrated that oncolytic adenovirus, whose replication was regulated by MREs, may be promising biological agents for glioma treatment.
authors.affiliation: Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.
authors.forename: Guocai
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.
authors.forename: Quanqin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Fan
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China. Electronic address: yonglibo@gmail.com.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Bo
mesh_terms: D000256:Adenoviridae; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000628:therapy*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D020218:Response Elements / Q000235:genetics*
chemical_list: D035683:MicroRNAs
keywords: Adenovirus; Glioma; miRNA