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Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer

Gene Therapy volume 11, pages 187–193 (2004)Cite this article

Abstract

Activator protein-1 (AP-1), a transcription factor, is activated through many oncogenic signals. However, its biological role in colorectal cancer has not been fully elucidated. To investigate the role of AP-1 in colorectal cancer, we constructed an adenovirus-expressing TAM67, a dominant-negative mutant of c-Jun lacking the transactivation domain of wild c-Jun (DN-c-Jun), to inhibit endogenous AP-1. AP-1 DNA-binding activity was increased in colon cancer cells (HT-29 cells) by serum stimulation, followed by an increase in both [3H]thymidine incorporation and cell number. Transfection of Ad-DN-c-Jun to HT-29 cells significantly inhibited serum-induced cell proliferation in vitro. As shown by flow cytometric analysis, DN-c-Jun significantly inhibited entrance into S phase after serum stimulation, thereby leading to G1 arrest. In vivo transfection of Ad-DN-c-Jun into xenografted HT-29 cell tumors in nude mice significantly decreased tumor volume on day 21 after treatment. A change was associated with decrease in Ki-67 labeling index. These observations together showed that AP-1 is a critical modulator for proliferation and cell cycle of HT-29 cells. We obtained the first evidence that DN-c-Jun gene transfer exerted a significant antitumor effect on colon cancer both in vitro and in vivo. DN-c-Jun gene transfer may be a new candidate for treatment of colorectal cancer.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, Osaka City University Medical School, Abeno-ku, Osaka, Japan

    R Suto, K Tominaga, E Sasaki, K Higuchi & T Arakawa

  2. Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan

    H Mizuguchi

  3. Department of Pharmacology, Graduate School of Medicine, Osaka City University Medical School, Abeno-ku, Osaka, Japan

    S Kim & H Iwao

Authors
  1. R Suto
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  2. K Tominaga
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  4. E Sasaki
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  5. K Higuchi
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  7. H Iwao
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  8. T Arakawa
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Suto, R., Tominaga, K., Mizuguchi, H. et al. Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer. Gene Ther 11, 187–193 (2004). https://doi.org/10.1038/sj.gt.3302158

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  • DOI: https://doi.org/10.1038/sj.gt.3302158

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