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Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44(+) gastric cancer cells via attenuating Wnt signaling.
MedLine Citation:
PMID:  23188090     Owner:  NLM     Status:  Publisher    
BACKGROUND: Gastric cancer stem cells (CSCs), which require activation of Wnt signaling to maintain their self-renewal and tumorigenicity, are proposed to be critical targets for effective therapy of gastric carcinomas. Gene therapies that are delivered by adenovirus of serotype 5 (Ad5) or chimeric 5/35(Ad5/35) adenovirus have shown promise for treating various cancers. Here we aimed to develop a gene therapy strategy that targeted gastric CSCs (CD44(+) cells). METHODS: CD44(+) cells were isolated by fluorescence activated cell sorting from both primary gastric cancer cells and cell lines. Expression of adenovirus receptors was examined in CD44(+) and CD44(-) cells. A potent Wnt antagonist Dickkopf-1 (DKK1) was delivered into CD44(+) cells using Ad5/35 (Ad5/35-DKK1). The therapeutic outcomes were evaluated. RESULTS: Expression of Coxsakievirus adenovirus receptor for Ad5 was significantly reduced, while abundance of CD46, the receptor for Ad5/35, was slightly higher in CD44(+) cells. Accordingly, CD44(+) cells were sensitive to Ad5/35 infection, but not to Ad5. Ad5/35-DKK1 introduced DKK1 into CD44(+) cells and deactivated endogenous Wnt/β-catenin signaling efficiently. Overexpression of DKK1 inhibited survival, anchorage-independent colony formation, and invasion of CD44(+) cells, which were restored by a GSK-3 specific inhibitor BIO-acetoxime. More importantly, introduction of DKK1 abrogated the tumorigenicity of CD44(+) cells in vivo. However, Ad5/35-DKK1 only showed minimal cytotoxicity to normal tissue-derived cells, L-02 and GES-1. CONCLUSIONS: We developed, for the first time, a novel Ad5/35-DKK1-based approach to abrogate Wnt signaling in CSCs and demonstrated that gastric CSC-targeting gene therapy was effective in preclinical experiments.
Bin Wang; Jia Liu; Lei Na Ma; Hua Liang Xiao; Ya Zhou Wang; Yan Li; Zhe Wang; Linli Fan; Chunhui Lan; Min Yang; Lu Hu; Yanlin Wei; Xiu Wu Bian; Dongfeng Chen; Jun Wang
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-28
Journal Detail:
Title:  Journal of gastroenterology     Volume:  -     ISSN:  1435-5922     ISO Abbreviation:  J. Gastroenterol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9430794     Medline TA:  J Gastroenterol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
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