Abstract
The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Carcinoma, Hepatocellular / immunology
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / therapy*
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Cell Proliferation
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Cell Survival
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Cytotoxicity, Immunologic
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G1 Phase Cell Cycle Checkpoints
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Gene Expression Profiling
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Gene Knockdown Techniques
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Genetic Therapy
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Genetic Vectors
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Green Fluorescent Proteins / biosynthesis
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Green Fluorescent Proteins / genetics
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Killer Cells, Natural / immunology
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Killer Cells, Natural / physiology
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Liver Neoplasms / immunology
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms / therapy*
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Mice
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Plasmids
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RNA Interference
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RNA, Small Interfering / genetics*
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Salmonella typhimurium / genetics*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / physiology
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Tumor Burden
Substances
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RNA, Small Interfering
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Recombinant Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Green Fluorescent Proteins