title: Use of microRNA Let-7 to control the replication specificity of oncolytic adenovirus in hepatocellular carcinoma cells.
abstract: Highly selective therapy for hepatocellular carcinoma (HCC) remains an unmet medical need. In present study, we found that the tumor suppressor microRNA, let-7 was significantly downregulated in a proportion of primary HCC tissues (12 of 33, 36.4%) and HCC cell lines. In line with this finding, we have engineered a chimeric Ad5/11 fiber oncolytic adenovirus, SG7011(let7T), by introducing eight copies of let-7 target sites (let7T) into the 3' untranslated region of E1A, a key gene associated with adenoviral replication. The results showed that the E1A expression (both RNA and protein levels) of the SG7011(let7T) was tightly regulated according to the endogenous expression level of the let-7. As contrasted with the wild-type adenovirus and the control virus, the replication of SG7011(let7T) was distinctly inhibited in normal liver cells lines (i.e. L-02 and WRL-68) expressing high level of let-7 (>300 folds), whereas was almost not impaired in HCC cells (i.e. Hep3B and PLC/PRF/5) with low level of let-7. Consequently, the cytotoxicity of SG7011(let7T) to normal liver cells was successfully decreased while was almost not attenuated in HCC cells in vitro. The antitumor ability of SG7011(let7T)in vivo was maintained in mice with Hep3B xenograft tumor, whereas was greatly decreased against the SMMC-7721 xenograft tumor expressing a high level of let-7 similar with L-02 when compared to the wild-type adenovirus. These results suggested that SG7011(let7T) may be a promising anticancer agent or vector to mediate the expression of therapeutic gene, broadly applicable in the treatment for HCC and other cancers where the let-7 gene is downregulated.
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.forename: Saiqun
authors.initials: S
authors.lastname: Lv
authors.forename: Jiahe
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Hu
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhou
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Huang
authors.forename: Linfang
authors.initials: L
authors.lastname: Li
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000235:genetics / Q000517:prevention & control / Q000821:virology*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000517:prevention & control / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control / Q000821:virology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D050130:Oncolytic Virotherapy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; C487931:mirnlet7 microRNA, human; D049452:Green Fluorescent Proteins; D008156:Luciferases