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STAT1 Activation-Induced Apoptosis of Esophageal Squamous Cell Carcinoma Cells In Vivo

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ABSTRACT

Background

The induction of apoptosis might be a promising treatment for cancers refractory to conventional therapies, such as esophageal cancer. In this study, we examined whether epidermal growth factor–induced growth inhibition results from apoptosis of esophageal squamous cell carcinoma (SCC) cells as a result of STAT1 activation and evaluated whether interferon gamma (IFN-γ) can induce apoptosis of cancer cells in vivo.

Methods

To assess the function of STAT1, we established stable transfectants expressing dominant-negative STAT1. Apoptosis was assessed by several experimental techniques, including flow cytometry. Differentiation was evaluated by Western blot test with involucrin used as a marker. In vivo, cancer cells were injected into male BALB/c nu/nu mice. Two weeks later, the mice started to receive injections of IFN-γ or saline into a tail vein four times per week. Concentrations of IFN-γ in the tumors were analyzed by enzyme-linked immunosorbent assay. Apoptosis was evaluated by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining.

Results

Epidermal growth factor inhibited the growth of esophageal SCC cells by causing apoptosis through several pathways involving STAT1 activation. IFN-γ induced the apoptosis of cancer cells, but it also promoted the differentiation (not apoptosis) of primary cultured cells derived from normal esophageal epithelium. IFN-γ also inhibited the growth of xenograft tumors of esophageal SCC cells in vivo.

Conclusions

Our results suggest that IFN-γ is one candidate for cytokine-based therapy of cancer. IFN-γ–induced STAT1 activation might be involved in the apoptosis of esophageal SCC cells and in the terminal differentiation of normal squamous cells. Further studies of STAT1 signaling pathways may provide the basis for new targeted therapeutic strategies for esophageal SCC.

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Acknowledgments

Supported by grants-in-aid from the Japanese Ministry of Education, Science and Culture (10470241, 11877197, G.W.) and by the Public Trust Haraguchi Memorial Cancer Research Fund and the Uehara Memorial Life Science Fund. All animal experiments were performed in accordance with Kyoto University guidelines. We thank Dr. K. Nakajima and Dr. T. Hirano (Department of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, Osaka, Japan) for providing DN-Stat1F vector; Dr. J. Miyazaki (Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka) for providing pCAG vector; T. Welte, A. Kano, and J. Moth for reading the article in manuscript and for their interesting discussion; S. Shimada for culturing cells; and Y. Nishimura and Y. Moriwaki for assistance.

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan

    Junichi Kaganoi MD, PhD, Go Watanabe MD, PhD, Michio Okabe MD, Shiro Nagatani MD, Atsushi Kawabe MD, PhD, Yutaka Shimada MD, PhD & Yoshiharu Sakai MD, PhD

  2. Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan

    Junichi Kaganoi MD, PhD

  3. Osaka Saiseikai Noe Hospital, Imafukuhigashi, Zyoto-ku, Osaka, 536-0002, Japan

    Masayuki Imamura MD, PhD

Authors
  1. Junichi Kaganoi MD, PhD
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  2. Go Watanabe MD, PhD
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  3. Michio Okabe MD
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  4. Shiro Nagatani MD
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  5. Atsushi Kawabe MD, PhD
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  6. Yutaka Shimada MD, PhD
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  7. Masayuki Imamura MD, PhD
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  8. Yoshiharu Sakai MD, PhD
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Corresponding author

Correspondence to Go Watanabe MD, PhD.

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Kaganoi, J., Watanabe, G., Okabe, M. et al. STAT1 Activation-Induced Apoptosis of Esophageal Squamous Cell Carcinoma Cells In Vivo. Ann Surg Oncol 14, 1405–1415 (2007). https://doi.org/10.1245/s10434-006-9274-7

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  • DOI: https://doi.org/10.1245/s10434-006-9274-7

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