title: Antitumor activity and inhibitory effects on cancer stem cell-like properties of Adeno-associated virus (AAV) -mediated Bmi-1 interference driven by Bmi-1 promoter for gastric cancer.
abstract: Bmi-1 is aberrantly activated in various cancers and plays a vital role in maintaining the self-renewal of stem cells. Our previous research revealed that Bmi-1 was overexpressed in gastric cancer (GC) and it's overexpression was an independent negative prognostic factor, suggesting it can be a therapeutic target. The main purpose of this investigation was to explore the antitumor activity of Bmi-1 interference driven by its own promoter (Ad-Bmi-1i) for GC. In this study, we used adenoviral vector to deliver Bmi-1 shRNA driven by its own promoter to treat GC. Our results revealed that Ad-Bmi-1i could selectively silence Bmi-1 in GC cells which overexpress Bmi-1 and suppress the malignant phenotypes and stem-like properties of GC cells in vitro and in vivo. Moreover, direct injection of Ad-Bmi-1i into xenografts suppressed tumor growth and destroyed cancer cells in vivo. Ad-Bmi-1i inhibited the proliferation of GC cells mainly via inducing senescence in vitro, but it suppressed tumor through inducing senescence and apoptosis, and inhibiting angiogenesis in vivo. Bmi-1 knockdown by Ad-Bmi-1i downregulated VEGF via inhibiting AKT activity. These results suggest that Ad-Bmi-1i not only inhibits tumor growth and stem cell-like phenotype by inducing cellular senescence directly, but also has an indirect anti-tumor activity by anti-angiogenesis effects via regulating PTEN/AKT/VEGF pathway. Transfer of gene interference guided by its own promoter by an adeno-associated virus (AAV) vector might be a potent antitumor approach for cancer therapy.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Weijian
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yufan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|Shanghai Tianyou Hospital of Tongji University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus; D055785:Gene Knockdown Techniques / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: C069077:BMI1 protein, human; D034741:RNA, Small Interfering; D063150:Polycomb Repressive Complex 1
keywords: Bmi-1; RNA interference; cancer stem cell; gastric cancer