title: Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis.
abstract: The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential tumor-suppressive effects via multiple pathways. However, the therapeutic effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer in human osteosarcoma is still unknown. In this study, we explored the in vitro and in vivo antitumor activity of Ad-ING4 in human osteosarcoma and its potential mechanism using a MG-63 human osteosarcoma cell line. We demonstrated that Ad-ING4 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27 and Bax, downregulated the Bcl-2 expression and activated Caspase-3 in MG-63 human osteosarcoma cells. Moreover, intratumoral injections of Ad-ING4 in athymic nude mice bearing MG-63 human osteosarcoma tumors significantly suppressed osteosarcoma xenografted tumor growth, increased the expression of P21, P27 and Bax, reduced the Bcl-2 and CD34 expression and microvessel density (MVD) in tumors. This retarded MG-63 osteosarcoma growth in vitro and in vivo in an athymic nude mouse model elicited by Ad-ING4 was closely associated with the increase in the expression of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to pro-apoptotic molecules Bcl-2/Bax followed by the activation of Caspase-3 leading to apoptosis via intrinsic apoptotic pathways, and the inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 is a potential candidate for human osteosarcoma gene therapy.
authors.affiliation: Department of Orthopedics, First Affiliated Hospital of Soochow University, No. 188, Shizi Road, Suzhou 215006, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Soochow University, No. 188, Shizi Road, Suzhou 215006, PR China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Cell Biology, School of Medicine, Soochow University, No. 1, Shizi Road, Suzhou 215123, PR China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Sheng
authors.affiliation: Department of Cell Biology, School of Medicine, Soochow University, No. 1, Shizi Road, Suzhou 215123, PR China.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Cell Biology, School of Medicine, Soochow University, No. 1, Shizi Road, Suzhou 215123, PR China jcyang@suda.edu.cn.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D025521:Tumor Suppressor Proteins
keywords: Adenoviral vector; Angiogenesis; Apoptosis; ING4; Osteosarcoma