Oncotarget

Research Papers:

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

Xiaowei Zhang, Weijian Guo, Xiaofeng Wang, Xinyang Liu, Mingzhu Huang, Lu Gan, Yufan Cheng and Jin Li _

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Oncotarget. 2016; 7:22733-22745. https://doi.org/10.18632/oncotarget.8174

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Abstract

Xiaowei Zhang1,*, Weijian Guo1,*, Xiaofeng Wang1, Xinyang Liu1, Mingzhu Huang1, Lu Gan1, Yufan Cheng1, Jin Li1,2

1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

2Shanghai Tianyou Hospital of Tongji University, Shanghai, China

*These authors contributed equally to this work

Correspondence to:

Jin Li, e-mail: [email protected]

Keywords: Bmi-1, RNA interference, gastric cancer, cancer stem cell

Received: July 20, 2015     Accepted: February 15, 2016     Published: March 18, 2016

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.


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