title: Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model.
abstract: It has been demonstrated that numerous microRNAs (miRNAs) have potent tumor-suppressing effects on a variety of cancers, implicating a possible application of miRNA in tumor therapy. Oncolytic adenovirus is a suitable vector to deliver tumor suppressor genes for treatment of cancers. However, it remains unknown whether co-expression of tumor suppressor genes and miRNAs can contribute to a more potent antitumor capacity within an oncolytic adenovirus delivery system. In this study, we found that expression of miRNA-34a was reduced in hepatocellular carcinoma (HCC), and the reduced expression of miRNA-34a was associated with worse outcome of HCC patients. Thus, we developed an oncolytic adenoviral vector, AdCN205, to co-express miRNA-34a and IL-24 driven by an adenovirus endogenous E3 promoter in HCC cells. High levels of miRNA-34a and IL-24 expression were detected in AdCN205-IL-24-miR-34a-infected HCC cells. AdCN205-IL-24-miR-34a significantly induced dramatic antitumor activity, as compared with that induced by AdCN205-IL-24 or AdCN205-miR-34a alone. Transfer of miRNA-34a into HCC cells inhibited the expression of its target genes, Bcl-2 and SIRT1. Treatment of established xenograft HCC tumors with AdCN205-IL-24-miR-34a in a mouse model resulted in complete tumor regression without recurrence. Taken together, our data provide a promising and reasonable delivery strategy of double-aimed cancer therapy, in which miRNAs and tumor-suppressing genes are used simultaneously.
authors.affiliation: Lab. of Biotherapy of Cancer, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Lou
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Leina
authors.initials: L
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.forename: Youhong
authors.initials: Y
authors.lastname: Cui
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D050504:Oncolytic Viruses / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; C447939:SIRT1 protein, human; D056564:Sirtuin 1