title: Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells.
abstract: Oncolytic viruses have recently received widespread attention for their potential in innovative cancer therapy. Many telomerase promoter-regulated oncolytic adenoviral vectors retain E1A and E1B. However, the functions of E1A and E1B proteins in the oncolytic role of replication-competent adenovirus (RCAd) and RCAd enhanced transduction of replication defective adenoviruses (RDAd) have not been addressed well. In this study, we constructed viruses expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa. We then tested their roles in oncolysis and replication of RCAd as well as their roles in RCAd enhanced transfection rate and transgene expression of RDAd in various cancer cells in vitro and in xenografted human NCI-H460 tumors in nude mice. We demonstrated that RCAds expressing E1A alone and plus E1B-19 kDa exhibited an obvious ability in replication and oncolytic effects as well as enhanced RDAd replication and transgene expression, with the former showed more effective oncolysis, while the latter exhibited superior viral replication and transgene promotion activity. However, RCAd expressing both E1A and E1B-19 kDa/55 kDa was clearly worst in all these abilities. The effects of E1A and E1B observed through using RCAd were further validated by using plasmids expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa proteins. Our study provided evidence that E1A was essential for inducing replication and oncolytic effects of RCAd as well as RCAd enhanced RDAd transduction, and expression of E1B-19 kDa other than E1B-55 kDa could promote these effects. E1B-55 kDa is not necessary for the oncolytic effects of adenoviruses and somehow inhibits RCAd-mediated RDAd replication and transgene expression.
authors.affiliation: Experimental Research Center; First People's Hospital; Shanghai Jiaotong University School of Medicine; Shanghai, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Experimental Research Center; First People's Hospital; Shanghai Jiaotong University School of Medicine; Shanghai, PR China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: Experimental Research Center; First People's Hospital; Shanghai Jiaotong University School of Medicine; Shanghai, PR China.
authors.forename: Xiafang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Dermatology; Duke University Medical Center; Durham, NC USA.
authors.forename: Chuanyuan
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Center; First People's Hospital; Shanghai Jiaotong University School of Medicine; Shanghai, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005822:Genetic Vectors; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy; D014161:Transduction, Genetic; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins
keywords: adenoviral vector; gene expression; gene transduction; replication competent adenovirus; replication defective adenovirus; tumor; tumor gene therapy