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

Gene Ther. 2004 Jan;11(2):187-93. doi: 10.1038/


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.

MeSH terms

  • Animals
  • Cell Division
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / therapy*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Genetic Therapy / methods*
  • HT29 Cells
  • Humans
  • Injections, Intralesional
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-jun / genetics*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Transcription Factor AP-1 / metabolism*
  • Transfection / methods


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1