title: Adeno-associated virus mediated gene transfer of Shepherdin inhibits gallbladder carcinoma growth in vitro and in vivo.
abstract: Gene therapy, a significantly crucial strategy for treatment of malignancies, has been gradually accepted in recent years. However, this therapeutic approach has being facing great challenges concerning problems which include complicated development of cancer with multiple gene control, effective target shortage, low efficiency of gene transferring and safety of the vector delivery system. Shepherdin, a novel peptidomimetic molecule designed from Lys-79 to Leu-87 of survivin, has been identified as a tumor suppressor with the function that can not only competitively interfere with the interaction between survivin and Hsp90 (heat shock protein-90) leading to the degradation of survivin to anti-tumor, but also competitively target the ATP-dependent binding pocket of Hsp90 resulting in the dysfunction of Hsp90 chaperone to cell apoptosis via a mitochondrial dependent or independent pathway. In the present study, we designed and constructed a recombinant Adeno-associated virus (rAAV) loading fusion gene NT4-TAT-6His-Shepherdin. The expression of Shepherdin in gallbladder carcinoma (GBC) cells was detected and its strong inhibitory effects against GBC growth were evaluated after AAV mediated gene transfer of Shepherdin into GBC cells and xenograft tumors. MTT assay and flow cytometric analysis demonstrated that rAAV containing Shepherdin gene could significantly inhibit the growth of GBC and this effect was closely associated with apoptosis. These results indicated that rAAV-NT4-TAT-6His-Shepherdin may be considered a novel therapeutic strategy in the gene therapy for gallbladder carcinoma.
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin 300162, China. Electronic address: zhaj_1023@163.com.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Oncology Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Logistics University of the Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: Dongchang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Xi'an Huaguang Bio-engineering Company, Xi'an 710025, China.
authors.forename: Guangxiao
authors.initials: G
authors.lastname: Yang
authors.affiliation: Xi'an Huaguang Bio-engineering Company, Xi'an 710025, China.
authors.forename: Quanying
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004274:DNA, Recombinant / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000235:genetics* / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D004274:DNA, Recombinant; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; C503112:shepherdin
keywords: Apoptosis; Gallbladder carcinoma; Gene therapy; Shepherdin