title: Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma.
abstract: Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM.
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lei
authors.affiliation: Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, 310014, P.R. China.
authors.forename: Shibing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Xianbo
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, 310006, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, P.R. China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D045304:Cytochromes c