1. Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer
- Author
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Kazuhide Higuchi, Hiroshi Iwao, Shokei Kim, Eiji Sasaki, Tetsuo Arakawa, Kazunari Tominaga, Reiko Suto, and H Mizuguchi
- Subjects
Proto-Oncogene Proteins c-jun ,Cell ,Mice, Nude ,Mouse model of colorectal and intestinal cancer ,Biology ,Injections, Intralesional ,Transfection ,Transactivation ,Mice ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Cell growth ,c-jun ,Genetic transfer ,Genetic Therapy ,Cell cycle ,DNA-Binding Proteins ,Transcription Factor AP-1 ,medicine.anatomical_structure ,Immunology ,Mutation ,Cancer research ,Molecular Medicine ,Female ,Colorectal Neoplasms ,HT29 Cells ,Cell Division ,Neoplasm Transplantation - 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 [(3)H]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 G(1) 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.
- Published
- 2004