title: Cancer targeting gene-viro-therapy specific for liver cancer by α-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24.
abstract: The combination of gene therapy and virotherapy for cancer treatment has received close attention and has become a trend in the field of cancer biotherapy. A strategy called 'Cancer Targeting Gene-Viro-Therapy' (CTGVT) or 'Gene Armed Oncolytic Viral Therapy' (GAOVT) has been proposed, in which an antitumor gene is inserted into an oncolytic viral vector. In our previous study, a dual-regulated oncolytic adenovirus with enhanced safety for normal cells and strict liver cancer-targeting ability, designated Ad•enAFP•E1A•E1B (Δ55) (briefly Ad•enAFP•D55), was successfully constructed. In the current work, interleukin-24 (IL-24) and suppressor of cytokine signaling 3 (SOCS3) genes were packaged into Ad•enAFP•D55. The new constructs, Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3), showed improved tumoricidal activity in hepatoma cell lines compared with the oncolytic viral vector Ad•enAFP•D55. The co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) showed much better antitumor effect than Ad•enAFP•D55-(IL-24) or Ad•enAFP•D55-(SOCS3) alone both in vitro and in a nude mouse xenograft model. Moreover, our results also showed that blockade of the Jak/Stat3 pathway by Ad•enAFP•D55-(SOCS3) infection in HuH-7 cells could down-regulate some anti-apoptosis proteins, such as XIAP, Bcl-xL, and survivin, which might sensitize the cells to Ad•enAFP•D55-(IL-24)-induced apoptosis. These results indicate that co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) may serve as a candidate therapeutic approach for the treatment of liver cancer.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Ruicheng
authors.initials: R
authors.lastname: Wei
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Hongling
authors.initials: H
authors.lastname: Huang
authors.forename: Miao
authors.initials: M
authors.lastname: Ding
authors.forename: Kangjian
authors.initials: K
authors.lastname: Zhang
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000494:pharmacology*; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000509:alpha-Fetoproteins; D000099180:Interleukin-24; C106644:SOCS3 protein, human